16-alkylidene pregnanes and process for their manufacture



United States Patent 3,519,619 16-ALKYLIDENE PREGNANES AND PROCESS FORTHEIR MANUFACTURE Emanuel B. Hershberg, West Orange, Eugene P. Oliveto,

Glen Ridge, and Richard C. Rausser, Union, N..I., assignors to ScheringCorporation, Bloomfield, N.J., a corporation of New Jersey N0 Drawing.Continuation-impart of applications Ser. N 0. 861,207, and Ser. No.861,208, both filed Dec. 22, 1959. This application Jan. 20, 1967, Ser.No. 610,474

Int. Cl. C07c 173/00 US. Cl. 260239.55 21 Claims ABSTRACT OF THEDISCLOSURE Novel 3-oxygenated-16-alkylidene 17oz hydroxy-20-keto-pregnanes and esters thereof, useful mainly as intermediates in thepreparation of 16-alkylidene-progesterones and l6-alkylidene-corticoidshaving a valuable pharmaco logical properties, are prepared via a novelprocess whereby a 3-oxygenated-16-alky1-20-keto-l6-dehydropregname istreated with an expoxidation reagent, preferably hydrogen peroxide in analkaline medium, and the novel 3-oxygenated-16 8-alkyl 16a,17moxido-ZO-keto-pregnane thereby produced or a derivative thereof istreated with a strong, non-oxidizing acid in a non-aqueous solvent,preferably hydrogen bromide in acetic acid.

This application is a continuation-in-part of copending applicationsSer. Nos. 861,207 now abandoned and 861,- 208 now US. Pat. No. 3,312,692of Eugene P. Oli'veto, Richard Rausser, and Emanuel Hershberg filed Dec.22,

This invention relates to compositions of matter which may be classifiedin the art of chemistry as 16-alkylidenepregnanes, to methods for theirmanufacture, and to novel intermediates produced thereby. Moreparticularly, this invention relates to the preparation of 16-loweralkylidene progesterones and 16-lower alkylidene corticoids which aretherapeutically active per se and are also valuable as intermediates.This invention also relates to 3,17a-dihydroxy-16-lower alkylidenecompounds of the pregnane series (e.g.l6-methylene-17a-hydroxy-pregnenolone) which are valuable mainly asintermediates in the preparation of the aforementioned 16-loweralkylidene-progesterones and l6-lower alkylidene-corticoids; alsoincluded in this invention are 16a,17a-oxido-16;8- lower alkyl pregnaneintermediates in the preparation of the l6-lower alkylidene compounds.

The invention sought to be patented, in one of its composition aspects,is described as residing in the concept of a chemical compound having amolecular structure in which there is attached to a 20-keto-pregnanenucleus, an exocyclic lower alkylidene at C-16, an alpha hydroxy (orlower alkanoyloxy) at 017, and an oxygenated function at C-3 (preferablya hydroxy or a hydrocarbon carboxylic acid ester thereof), which 20keto-pregnane nucleus may possess other nuclear substituents and nuclearsaturated and nuclear unsaturated systems. The 3-hydroxy-16-loweralkylidene pregnanes of this composition aspect of our invention areuseful mainly as intermediates in preparing the therapeutically active16-lower alkylidene progesterones and 16-lower alkylidene corticoids.

The invention sought to be patented in another of its compositionaspects is described as residing in the concept of a chemical compoundhaving a molecular structure in which there is attatched to a20-keto-pregnane nucleus, a beta lower alkyl group at 016, analpha-epoxy group at C-16 and C-17, an oxygenated function at C-3(preferably Patented July 7, 1970 hydroxy or carboxylic acid esterthereof or a ketonic oxygen), which 20-keto-pregnane nucleus may possessother nuclear substituents and nuclear saturated and nuclear unsaturatedsystems. The compounds of this composition aspect are useful asintermediates for preparing the 16- lower alkylidene intermediates ofthis invention as well as therapeutically active 16-lo:weralkylidene-17ot-hydroxyprogesterones and l6-lower alkylidene-lh-hydroxycorticoids.

The invention sought to be patented in its process aspect is describedas residing in the concept of preparing a 16a,17a-epoxy derivative of a16-lower alkyl-20-keto-16- dehydro compound of the pregnane series, andtreating the resulting 16a,17a-oxido-16,8-lower alkyl-20-keto-compoundof the pregnane series with a non-oxidizing strong acid whereby cleavageof the 16a,17a-epoxy function is effected and there is formed a 16-loweralkylidene-17oz-hydroxy-20-keto compound of the pregnane series, i.e. a16- lower alkylidene compound of the composition aspect of thisinvention. Preferred among the non-oxidizing strong acids contemplatedfor use in the process aspect of this invention are the hydrogenhalides, and particularly hydrogen bromide. In the process aspect ofthis invention, the 1606,17tX-CPOXY derivatives are preferably preparedvia the action of alkaline hydrogen peroxide on a 16-loweralkyl-20-keto-l6-dehydropregnane.

The present invention is based upon the surprising dis covery that, intwo steps, one can convert a l6-lower alkyl-ZO-keto-l6-dehydro-pregnaneinto a 16-lower alkylidene-l7u-hydroxy-20-keto-pregnane, and that thisreaction is not affected to any substantial degree by the presence ofother substituents in the pregnane molecule.

The term pregnane as used in this specification and in the claimsincludes both nuclearly saturated and nuclearly unsaturated compoundsexcept where otherwise indicated. The term pregnane thus includesunsaturated derivatives such as l-pregnenes, 4-pregnenes, 6-pregnenes,1,4-pregnadienes, 4,6-pregnadienes, 1,4,6-pregnatrienes, 5- pregnenes,9(11)-pregnenes and the like.

The manner and process of making and using the invention will now begenerally described so as to enable a person skilled in the art ofchemistry to make and use the same as follows:

The necessary intermediates for the process aspect of this invention,i.e. the 16 8-lower alkyl-16u,17a-oxido-20- keto-pregnanes of theinvention are conveniently and preferably prepared from thecorresponding 16-lower alkyl-16- dehydro-pregnanes upon treatment withalkaline hydrogen peroxide. Some of the requisite l6-loweralkyl-16-dehydropregnane starting materials are known, e.g. 16-methyl-5,16-pregnadien-3/3-ol-20-one. Other 16-lower alkyl-16- dehydropregnanestarting compounds may be prepared from known compounds employingprocedures well known in the art. For example, the known5,16-pregnadien-3fiol-20-one S-acetate upon treatment with a diazo loweralkane, e.g. diazomethane, followed by pyrolysis of the16a,17u-alkylenediazo intermediate, is converted to 16-methyl-5,l6-pregnadien-3fi-ol-20-one 3-acetate. By employing differentdiazo lower alkanes, there may be introduced other lower alkyl groups inthe 16-position as, for example, the ethyl or butyl groups.

Alternatively, the requisite 16-alkyl-16-dehydro-starting compounds maybe prepared from known 16-des-alkylprecursors, e.g. 5,l6-pregnadien-38-ol-20-one 3-acetate, by reaction with a suitable alkyl magnesiumhalide such as ethyl magnesium iodide in the presence of copper salt toyield the corresponding l6-alkyl-5-pregnane, e.g.16aethyl-5-pregnen-3B-ol-20-one. Esterification of the 3-hydroxyl iseffected by acetic anhydride in pyridine yielding16u-ethyl-5-pregnen-313-01-20-one 3-acetate. Bromination at 0-17 (withconcomitant addition of bromide at C-5 and 06 followed by sodium iodidetreatment to regenerate the double bond) by means of bromine in aceticacid followed by dehydrobromination of the thus formed l6u-ethyl-17wbromo-5-pregnen-3l3-ol-20-one 3-acetate with a basic agent such ascollidine, dimethylformamide, lutidine or the like yields the requisite16-alkyl-A -intermediate, 16-ethyl- 5,16-pregnadien-3fl-ol-ZO-one3-acetate.

By a suitable choice of Grignard reagent when preparing the necessaryl6-alkyl-l6-dehydro-intermediates of our process, and desired 16-alkylcompound of the composition aspect of our invention may be obtained.Thus, reaction of 5,16-pregnadien-3B-ol-20-one with n-butyl magnesiumbromide and subsequent acetylation yields l6a-nbutyl-5-pregnen-33-ol-20-one 3-acetate. Bromination and dehydrobromination of thel6a-butyl-5-pregnene compounds as described above givesl6-n-butyl-5,l6-pregnadien-Bfl-ol-ZO-one 3-acetate which, whenepoxidized with alkaline hydrogen peroxide yields a necessaryintermediate of our process, e.g. l6 3-n-butyl-16a,17u-oxido-5-pregnen-3,6-ol-20-one. Oxidation of the 3-hydroxy-5-pregnene according to theOppenauer techniques employing aluminum isopropoxide affords thecorresponding progesterone (3-ketoA which when reacted according to ourprocess with hydrogen bromide yields a 16-butylidene compound of thisinvention, i.e. 16-butylidene-l7a-hydroxy-progesterone.

By our process, 16-lower alky1-20-keto-l6-pregnanes and allopregneneshaving an oxygenated function at 03, such as the 3-keto, 3-hydroxy (aand ,6), and the 3-lower alkanoyloxy compounds, can be converted to thecorresponding l6-lower alkylidine compound with concomitant introductionof the valuable 17a-hydroxy group in two basic steps of high yield. The3-hydroxy and 3-acyloxy compounds are the preferred starting compoundsand for convenience will be referred to as exemplary of such startingcompounds in the description hereinafter. In addition, for purposes ofrepresentation, methyl will be employed as typical of the lower alkylgroup, and methylene of the lower alkylidene group.

In the first step of the process aspect of our invention, a3-hydroxy-20-keto-l6-lower alkyl-16-pregnene or all pregnane, oralternatively, the 3-lower alkanoate thereof, e.g.l6-methyl-16-pregnen-3B-ol-20-one 3-acetate, is treated with anappropriate epoxidation reagent so as to introduce a 16,17-0xido (i.e.epoxy) group thus forming, e.g.16a,17a-oxido-1613-methyl-pregnan-35-ol-20-one 3-acetate. While any ofthe appropriate reagents which have been used in this respect may beemployed, we prefer to use hydrogen peroxide in alkaline medium. This wehave found to be specific for a 16(17)-d0uble bond when in conjugationwith a keto function as is present in the 20- position. Thus, ourreagent is selective when additional unsaturation is present as, forexample, between C- and C-6 in a 5,16-pregnadiene. For example,16-methyl-5,16- pregnadien-3fi-ol-20-one B-acetate upon reaction withalkaline hydrogen peroxide will selectively form an epoxy function atC-16,17 to produce 16a,17a-oxido-16 3-methyl- 5-pregnen-3fi-ol-20-one3-acetate.

Prior to the next step of our process, (i.e. treatment of the16a,l7a-epoxy-16-methyl-20-keto pregnane with a non-oxidizing strongacid), we have found it advantageous to esterify the hydroxyl group inthe 3-position if such group is not already esterified. Although thefree 3-hydroxyl compound can be employed, we have obtained higher yieldsand easier purification of the product in the case of the 3-acyloxycompound, presumably because of solubility differences. Any acyloxygroup may be employed and, although for purposes of representation, theacetate group will be used in the present description as being typical,it should be noted that other ester groups may be employed, such asother lower alkanoates including propionate and butyrate,p-toluenesulfonate, and aryl carboxylates such as benzoate, and thelike. Similarly, while the process is exemplified predominantly by thenormal pregnane series (i.e. Sti-hydrogen at C-5) it is equallyapplicable to the all opregnane series (i.e. Set-hydrogen at C5) as wellas in the 5-dehydro-pregnane series.

In the second step of the process aspect of this invention, thel6oc,17oc-OXidOl6/3-1OW6I alkyl 20-keto pregnane (e.g.16a,l7a-oxido-l6/3-methyl-pregnane-3fl-ol-20-one 3- acetate) prepared asdescribed hereinabove, is treated with a strong non-oxidizing acid andthere is prepared a 16- lower alkylidene-17a-hydroxy-ZO-keto-pregnane(e.g. 16- methylene-l7a-hydroxy-pregnan-3fi-ol-20-one 3-acetate).

Exemplary of the strong, non-oxidizing acids used are such as a hydrogenhalide, as for example, hydrogen bromide, hydrogen chloride, hydrogenfluoride, or hydrogen iodide. Alternatively, other acids may be employedas the cleaving agent, for example, p-toluenesulfonic acid,trifluoroacetic acid, sulfuric acid and the like. Of the foregoing,hydrogen bromide is the preferred acid for use in our process. Thequantity of acid employed may be as high as 1 mole per mole of steroidor preferably as low as 0.1 mole per mole of steroid. Under suchconditions the 16,17-epoxy function is opened to form the 17a-hydroxylgroup and concomitantly the l6-lower alkyl group is converted to a16-lo'wer alkylidene function.

The treatment of the l6fl-lower alkyl-l6a,l7a-oxido- ZO-keto pregnanewith strong acid is carried out in a suitable solvent such as loweralkanoic acids (preferably acetic acid), dioxane, benzene, toluene,xylene, tetrahydrofuran, dimethylformamide and the like. The temperatureof the reaction medium is preferably maintained below C., a range of 30to 60 C. being generally suitable.

As described above, points of unsaturation other than the A -bond may bepresent in the starting compounds when carrying out our process. Thus,when l6-n'1ethyl- 5,16-pregnadien-3/3-ol-20-one is subjected to theprocedures described above, there is formed l6-methylene-5- pregnene-3S,l7a-diol-20-one 3-acetate, a compound particularly valuable in thepreparation of l6-substituted derivatives of cortisone, prednisolone andrelated compounds. For example, this compound may be treated withbromine and the resulting 5,6,2l-tribromo derivative, then treated withsodium iodide so as to introduce an iodine atom in the 2l-position withconcomitant debromination at C-5 and C-6. Subsequent treatment with analkali metal lower alkanoate as, for example, potassium acetate thenyields the 2l-lower alkanoyloxy group. The 3-alkanoyloxy- S-dehydrosystem of the resulting 16-alkylidene compound, i.e.l6-methylene-5-pregnene-3/3,l7tx,2l-triol-20- one 3,2l-diacetate can bereadily converted to the 3-keto- 4-dehydro system by the action ofFlavobacterz'um dehydrogenans (see for example, Union of South AfricaPat. No. 3,462/55). The resulting l6-methylene-4-pregnene-17a,2l-diol-3,20-dione 2l-acetate is subjected to the action of Bacillussphaericus to convert the 4-pregnene into a 1,4-pregnadiene system.Finally hydroxylation at C-11 may be effected by the micro-organismCu'rvularizz lunata to yield 16-methyleneprednisolone.

By way of summary, our process preferably utilizes as starting compounda 3(0: and ,8)-hydroxy (or alkanoyloxy)-l6-methyl-20-keto 16dehydro-compound selected from the group consisting of the pregnane(5B), allopregnane (5a), and the S-dehydropregnane (S-pregnene) series.In a preferred mode of the process aspect of this invention there isfirst prepared a 16a,17a-oxido derivative of the aforementionedl6-methyl- 20 keto-16-dehydropregnanes by the action of alkalinehydrogen peroxide, and then the resultingl6B-methyl-l6a,l7a-oxido-20-ketopregnane intermediate of this inventionis treated with hydrogen bromide in acetic acid to form a 3(0: and ,8)-hydroxy (or alkanoyloxy)-16-methylene-17a-hydroxy-20- keto compoundselected from the group consisting of the pregnane (5B), allopregnane(5a) and S-dehydro-pregnane series (a16-methylene-l7a-hydroxy-20-ketopregnane of this invention).

Typical preferred starting compounds of the process aspect of thisinvention thus include: 16-methyl-16-pregnen-3a-ol-20-one and the3-acetate thereof, 16-methyl-16-allopregnen-3,8-ol-20-one and the3-acetate thereof,

16-methyl-16-pregnen-3fi-ol-20-one and the 3-acetate thereof,

16-methyll6-allopregnen-3 oc-Ol-ZQ-OHC and the 3-acetate thereof,

l6-methyl-5,16-pregnadien-3B-ol-20-one and the 3-acetate thereof, and

16-methyl-5,16-pregnadien-3 a-Ol-ZO-OIIC and the 3-acetate thereof.

By a preferred mode of our novel process as described hereinabove, theabove listed 3-hydroxy-pregnane starting compounds are transformed intothe following 16-methylene 17a hydroxy-pregnane 3 ols of the compositionaspects of this invention:

16-methylene-17a-hydroxy-pregnan-3a-oI-ZO-one and the 3-acetate thereof,

16-methylene-17a-hydroxy-allopregnan-3fi-ol-20-one and the 3-acetatethereof,

16-methylene 17a-hydroxy-pregnan-3fl-ol-20-one and the 3-acetatethereof,

l6-methylene-l7ot-hydroxy-allopregnan-3u-ol-20-one and the 3-acetatethereof,

l6-methylene-17a-hydroxy-5-pregnen-3p-ol-20-one and the 3-acetatethereof, and

l-methylene-l7a-hydroxy-5-pregnen-3 a-ol-20-one and the 3-acetatethereof.

Esters of the above 3-hydroxy-16-methylene-17a-hydroxy pregnanes of thecomposition aspect of this invention, i.e. the saturated 3X-l6-loweralkylidene-l7u-hydroxy-20-keto normal (i.e. the 5B) and allo (i.e. the50:) pregnanes, and the analogous S-pregnenes, wherein X represents thealkali metal salt of a partial polybasic acid ester group (e.g. thedisodium phosphate ester and the sodium succinyl ester group) are activeas intravenous anaesthetics in dosages common for other steroidintravenous anaesthetics.

The 3,l7a-dihydroXy-l6-lower alkylidene-ZO-keto-pregnames of ourinvention are valuable mainly as intermediates. Some representativemodifications of the foregoing 16-lower alkylidene-lh-hydroxy pregnaneshave already been described hereinabove, demonstrating their usefulnessas intermediates as, for example, the conversion of16-methylene-5-pregnene-3fl,17a-diol-20-one 3-acetate to16-methyleneprednisolone.

It is apparent that the key features of our invention in its processaspect involve modifications at 016 and 17 and the groups attachedthereto and that the applicability of the process is not affectedby thepresence of other groups elsewhere in the molecule. Furthermore, variousother known reactions can be effected after the introduction of thel6-lower alkylidene function by our process in addition to the oneillustrated above, whereby are prepared therapeutically valuable16-lower alkylidene 17ozhydroxy-progesterones and 16-loweralkylidene-lh-hydroxy corticoids which include 16 methylene 17 uhydroxy-ZO-keto-pregnanes represented by the following Formula I:

and include the 19-nor, l-dehydro, 6-dehydro and 1,6- bis-dehydroanalogs thereof wherein W is a member selected from the group consistingof hydrogen, methyl, and halogen, preferably chlorine and fluorine; X isa member selected from the group consisting of hydrogen and halogen; Yis a member selected from the group consisting of hydrogen, hydroxy,keto, acyloxy and halogen; and when Y is hydrogen, X is hydrogen; A is amember selected from the group consisting of hydrogen, hydroxy andacyloxy; R is a member selected from the group consisting of hydrogenand an alkyl radical having preferably up to four carbon atoms; and Z isa member of the group consisting of hydrogen, halogen (preferably iodineand fluorine) hydroxyl and acyloxy.

By the term acyloxy is contemplated hydrocarbon carboxylic acid radicalshaving up to eight carbon atoms, preferably lower alkanoic acids havingup to six carbon atoms. These preferred radicals are those obtained fromacids such as acetic, propionic, valeric, caproic, t-butylacetic, andthe like.

The alkyl radical designated by R in the general formula preferablyencompasses hydrocarbon radicals such as methyl, ethyl, n-propyl,isopropyl, n-butyl, sec.-butyl, and t-butyl, although higher homologssuch as pentyl and hexyl come within the scope of this invention.

When X and Y are both halogen, there is contemplated halogen pairs suchas (Cl, Cl), (Br, Br), (F, F), (Br, F), and the like.

In this specification, a bond shown as a curved or wavy line (3), suchas is shown at C-6, indicates that both the a and ,B-configurations areincluded. A compound name which does not specifically indicate the u orB-configuration implies the inclusion of both isomeric forms. Thus, thecompound name 6-methyl-1G-methyleneprogesterone includes the compounds6a-rnethy1-l6-methyleneprogesterone and6,6-methyl-l6-methyleneprogesterone.

Contemplated as being within the scope of the 16- methylene-lh-hydroxypregnanes prepared by the process aspect of this invention are 6, 17, or2l-monosubstituted, (6,17), (6,21), (17-21)-disubstituted,6,17,21-trisubstituted-16-lower alkylideneprogesterones, their 9,11-dihalogeno and ll-oxygenated derivatives as well as the 19-nor,l-dehydro, 6-dehydro and 1,6-bis-dehydro analogs thereof, and thecorresponding corticoid analogs having hydroxyl or lower alkanoyloxy atthe 21 carbon, with or without oxygen or hydroxyl at 0-11, and/ or9OL-halO- gen at the 09 position.

The novel compounds of the general Formula I, wherein Z is hydrogen orhalogen, as well as the 19-nor, 1- dehydro, 6-dehydro and1,6-bis-dehydro analogs thereof, are active progestational agents andare described in copending application Ser. No. 861,208 filed Dec. 22,1959, now US. Patent No. 3,312,692. When Z is hydroxy or acyloxy and the(3-11 is substituted by oxygen or Q- hydroxyl, the resulting 16-loweralkylene compounds possess cortical activity and are particularly usefulas antiinflammatory agents.

It has long been known that progesterone (the correspondingl'6-unsubstituted analog of our novel l6-methylene-progesterone) hasprogestational activity. Progesterone, however, has the disadvantage ofbeing therapeutically valuable only when administered parenterally.Surprisingly, our l6-lower alkylideneprogesterones are active whenadministered via both the parenteral and oral route. Moreover, l6-loweralkylideneprogesterones, such as 16-methyleneprogesterone,advantageously have a much greater potency than progesterone both whentaken orally or parenterally and can thus be administered in smallerdoses for equal effects.

Our novel 16-lower alkylideneprogesterones are preferably administeredorally in the form of tablets which may contain excipients such asstarch or sugar or other pharmaceutical carriers, or they can beadministered as in the form of suspensions for intramuscular andsubcutaneous administration.

Our 16-lower alkylideneprogesterones, in addition to being valuablepharmacologically, can be used also as intermediates in the preparationof other therapeutically active steroids. For example, a21-iodo-16-alkylideneprogesterone of the general Formula I, such asl6-methylenel7a-hydroxy-2l-iodoprogesterone, on treatment with a saltsuch as potassium acetate, is converted to a novel intermediate, i.e.16-methylene 4 pregnene-17a,21-dio1- 3,20-dione 21-acetate.Microbiological hydroxylation of the aforementioned intermediate at 011by known techniques with, for example, Curvularia lunata yields thenovel, therapeutically active 16-lower alkylidene-pregnane corticoid,16-methylenehydrocortisone (i.e. 16methylene- 4-pregnene-11p,'17a,21-triol-3,20-dione) The 16-lower alkylideneprogesterones definedby the general Formula I (except the l7u-hydroxyprogesterones which arevaluable mainly as intermediates) all possess the therapeutic activityas described above. The preferred 16-methyleneprogesterones of ourinvention are l6-methylene compounds possessing a l7-acyloxy group, andin particular those having hydrogen or an oxygenated function at thell-carbon. One of the preferred groups includes compounds such as16-methylene-17a-hydroxyprogesterone 17-acetate,6a-methyl-16-methylene-17a-acet0xyprogesterone, 6a-fiuoro- 16-methylene-17a-hydroxyprogesterone 17-caproate,6a-methyl-9u-bromo-11fl,17a-dihydroxyl6-methyleneprogesterone17-acetate, 6a-methyl-9a-fluoro-11-keto-16-methylene-17a-acetoxyprogesterone, 9ot-Chl0f0-11,8,17u-dihydroxy-16-methyleneprogesterone 11 formate l7-acetate, and1d-methylene-17a-acetoxy-2l-fluoroprogesterone. Some 9,11-dihalogenocompounds of the preferred 17a-acetoxy-16-methyleneprogesterones are9u,11B- dichloro- 1 6-methylene- 1 7a-acetoxy progesterone, 6u-methyl-9abromo-ll,8-fluoro-l6-methylene 17cc acetoxyprogesterone,6a,9a,11/3-trichloro-16-methylene-17u-acetoxyprogesterone,6a,2ldifiUOrO-9a,1lfi-diClllOlO 16 methylene 17oz acetoxyprogesterone,and 9a,1lfi difluoro-16- methylene-17fi-acetoxyprogesterone.

The 16-lower alkylidene-l7a-hydroxyprogesterones defined by Formula I,their l-dehydro, 6-dehydro, 1,6-bisdehydro and 19-nor analogs arevaluable mainly as intermediates in the preparation of the corresponding17aacyloxy analogs, which are active progestins. In addition, the 911,11,9-dihalogeno-2l-fluoro-16-alklidene-17a-hydroxyprogesterones of ourinvention, particularly their l-dehydro analogs, possessanti-inflammatory activity, thus rendering these compoundstherapeutically active per se.

By the process of this invention, there are also prepared l6-loweralkylidene corticoids, the preferred embodiment of which may berepresented as steroids of the group having the following structuralformula:

including the l-dehydro, 6-dehydro and 1,6-bis-dehydro analogs thereof,wherein R, W, X, Y are as defined for Formula I hereinabove, and R is amember of the group consisting of H and acyl radicals ofpharmaceutically acceptable acids including hydrocarbon monoanddi-carboxylic acids as well as inorganic acids such as phosphoric,sulfuric and other acids.

The manner is which the process and the composition aspects of thisinvention are utilized to prepare valuable16-methylene-17a-hydroxyprogesterones and l6-rnethylene corticoids ofFormulae I and II, will now be described I 8 as to enable a personskilled in the art of chemistry to make and use the same.

According to the process aspects of this invention, any steroidsmolecule possessing a 16-lower alkyl-16,17,oxido function, may beconverted by such process to the corresponding 16-loweralkylidene-17-hydroxy steroid. Thus, 168-methy1-16a,17a-oxidoprogesterone and9a-fiuOr0-16fimethyl-l6a,17a-oxido-4-pregnene-11pJ,2l-diol-3,20- dione21-acetate (prepared from 9a-fluorohydrocortisone 21- acetate byprocedures described hereinbelow and in our application Ser. No.861,211, now abandoned) when reacted with acetic acid and hydrogenbromide, will yield l6-methylene-l7a-hydroxyprogesterone and9u-fluoro-l6- methyleneprednisolone 2l-acetate, respectively.

Alternatively, the 16-alkylidene-17a-hydroxypregnanes of Formulae I andII are prepared from the 3-hydroxypregnane and the 3-hydroxy-5-pregneneprecursors, i.e. the 3-hydroxy-l6B-lower alkyl-16a,l7 ot-oxido-pregnaneand 5- pregnene intermediates of the composition aspect of thisinvention. Thus, 16,8-methyl-l6a,17a-oxido-5-pregnen-3 8- ol-20-one3-acetate when treated with acetic acid in the presence of hydrobromicacid yields l6-methylene-l7ahydroxy-S-pregnen-3fi-ol-20-one 3-acetate.Conversion of the 3-alkanoyloxy-5-dehydro system to the 3-keto-4-dehydrosystem can then be readily effected such as by the action of Flavobacterz'um dehydrogens to obtain16-methylene-l7a-hydroxyprogesterone.

Esterification of the hydroxyl function at the 17-carbon in16-methylene-17a-hydroxyprogesterone is conveniently eflFected with alower fatty acid anhydride such as acetic anhydride in the presence ofp-toluenesulfonic acid or, preferably, with a lower aliphatic acid suchas acetic acid in the presence of trifluoroacetic anhydride to give thecorresponding l7-ester, which in this case is l6-methylene-17a-acetoxyprogesterone. By substituting other lower alkanoic acids suchas caproic or B-cyclopentylpropionic for acetic in the aforementionedesterification procedures, other 17u-lower alkanoate 16-lower alkylidenecompounds are obtained such as the 17-caproate and the 17aS-cyclopentyl)-propionate, respectively, of16-methylene-l7a-hydroxyprogesterone.

The manner in which substituents at O6, 9, l1 and 21 as defined bymoieties R, W, X, Y and Z in Formulae I and II are introduced into thesteroid molecule is described below; the 16-loweralkylideneprogesterones being specifically discussed by way of example.

Iodine may be introduced in the 21-position of l6-loweralkylideneprogesterones such as 16-methylene-17u-hydroxyprogesterone byprocedures which utilize iodine in the presence of an alkaline substancesuch as sodium hydroxide or calcium oxide, thus producing21-iodo-16-lower alkylideneprogesterones of the general Formula I. Thel7a-hydroxy-2l-iodo substituted compound thus produced (e.g.16-methylene-17a-hydroxy-2l-iodoprogesterone) is conveniently convertedto a 16-methylene-17a-acyloxy-21- iodoprogesterone by the usualesterification techniques.

The 21 fluoro 16 lower alkylideneprogesterones are obtained from thecorresponding 21-iodo analogs by the action of silver fluoride in moistacetonitrile. For example,, 21 fluoro1G-methylene-17u-hydroxyprogesterone is derived from 21 iodo 16methylene-lh-hydroxyprogesterone.

The 21 fluoro 16 lower alkylidene-lh-lower alkanoate progesterones areconveniently prepared via an alternate route whereby iodine isintroduced (in a manner similar to that described hereinabove) at C-21of a 1604,1711 oxido precursor, e.g. 165 methyl :,1711-oxidoprogesterone, and in the 21-iodo derivative thus produced, e.g. 21iodo 16,8 mthy1-16cz,17a -0XidO- progesterone, the 21-iodo groupreplaced by 21-fluoro. The resulting 21 fluoro 1611,17 oxido-16B-methylintermediate, e.g. 21 fluoro 16a,17m oxido-165-methyl-progesterone upontreatment with an acid/acid anhydride mixture such as aceticacid/trifiuoroacetic anhydride utilizing techniques set forth in US.Pat. No.

3,168,537, is converted directly to a 16 alkylidene-lhalkanoyloxy 21fluoroprogesterone, e.g. 16 -.methylene- 17oz acetoxy 21fiuoroprogesterone. In the foregoing procedure, by substituting otherlower alkanoic acids, such as caproic and propionic, for acetic acid,there is obtained the corresponding 17 caproate and the l7-propionateester, e.g. 16 methylene 17a hydroxy-Zl-fluoroprogesterone 17 caproateand 17 propionate, respectively.

A 6-substituent is introduced into a 16-lower alkylidene progesterone toform novel 6 substituted 16- lower alkylidene progesterones by employingknown chemical techniques. Esterification of the 3 hydroxy group in apregnenolone compound such as l6B-methyl 16a,l7a oxidopregnene-3fl-ol-20-one with, for example, acetic anhydride in pyridine,yields the corresponding 3-acyloxy ester, i.e., 16p methyl 16a,17aoxido- 5 pregnen 3B ol--one 3-acetate. When the thus prepared 3-acetoxyester is treated with acetic acid and hydrobromic acid for example,there is formed the corresponding 16 methylene 3,8,17ocdihydroxy-S-pregnen 20 one 3-acetate. Treatment of the latter compoundwith ethylene glycol by known procedures yields the 20- ethylene ketalderivative which, in turn, is epoxidized on treatment with a peraeidsuch as peracetic or, preferably, monoperphthalic acid to give the epoxyderivative, 36,- 17oz dihydroxy 50:.60c epoxy 16-methylenepregnan- 20one 3 acetate 20 ethylene ketal. The 6-methyl substituent is introducedinto the pregnane nucleus by the addition to this epoxy derivative of aGrignard reagent such as methyl magnesium iodide which, with subsequenthydrolysis, yields a 5a-hydroxy-6-methyl intermediate, e.g. 35,511,170:trihydroxy 6B methyl-16-methylenepregnan 2O one ZO-ethylene ketal.Chromic acid oxidation converts the 3fi-hydroxypregnane to thecorresponding 3-ketopregnane, 5a,l7a dihydroxy 6B methyl-16-methylenepregnane-3,ZO-dione ZO-ethylene ketal. A reagent such asethanolic hydrochloric acid used on the aforementioned 3-ketopregnanesimultaneously dehydrates the 5a-hydroxy group, epimerizes the6fi-substitucut, and regenerates the 20-ketone to yield, for example, 6amethyl 16 methylene-17a-hydr0xyprogesterone. In order to obtain a 613configuration, a Set-hYdIOXY-613- substituted pregnane intermediate-(e.g. 50:,l7ot-dihYdIOXY- 6B methyl 16 methylenepregnane-3,20-dioneZO-ethylene ketal) is treated with, for example, thionyl chloride in acold basic medium such as pyridine or in approximately 90% acetic acidto give 16-alkylideneproges terones such as 6,8 methyl 16methylene-l7u-hydroxy progesterone ZO-ethylene ketal or 6,8 methyl17u-hydroxy 16 methylene-progesterone, respectively. A 60:- alkyl 16lower alkylideneprogesterone may also be prepared from the correspondingG S-substituted progesterone by means of alcoholic solutions of acids orbases such as ethanolic hydrogen chloride and ethanolic potassiumhydroxide.

When preparing a 6 alkyl l6 lower alkylidene-l7aacyloxypro-gesterone ofour invention, the 6-substituent may first be introduced into a17ot-hydroxy starting compound, followed by esterification of the 6substituted- 17a hydroxy 16 lower alkylideneprogesterone thereby formed.For example, 60c methyl 16 methylene-17a caprooxyprogesterone isobtained by first preparing 60cmethyl l6 methylenel7a-hydroxyprogesterone as shown above, followed by esterification byprocedures heretofore described, such as with caproic acid in thepresence of trifiuoroacetic anhydride, yielding the corresponding 17ozacyloxyprogesterone, e.g. 6a methyl-16- methylene 17acaprooxyprogesterone. Alternatively, the 6-substituent is introducedinto a 16-lower alkyl-16oz, 170t-OXldO starting compound which is thenreacted with a strong, non-oxidizing acid according to our process togive the corresponding 16-lower alkyl 16 methylene- 17ozhydroxyprogesterone which may then be esterified as describedhereinabove. Thus, 601,165 dimethyl 160:,

it 17a-oxidoprogesterone when treated with hydrogen bromide in aceticacid yields 60c methyl 16 methylenel7ot-hydroxyprogesterone which, upontreatment with caproic acid in the presence of tritluoroacetic anhydrideyields 6wmethyl 16 methylene 17a-caprooxyprogesterone.

Our 6-halogeno substituted progesterones are conveniently prepared from16 methylene 17w -hydroxypregnenolones such as 16 methylene 5pregnene-3fi, 17cc diol 20 one by addition of a halogenating agentacross the 5,6-double bond followed by oxidation of the 3-hydroxylfunction with, for example, chromic acid to the corresponding 3 keto 5,6dihalogeno-l6-methylenepregnane. Subsequent dehydrohalogenation of thelatter intermediates with sodium acetate yields the novel 6-halogenocompound, i.e. 6B halogeno 16 methylene-17a-hydroxyprogesterone.

When a 6 chloro 16 methyleneprogesterone is desired, a halogenatingagent such as chlorine or bromine chloride is employed with a Apregnenolone such as 16- methylene 5 pregnene 3fi,17a-diol-20-one toobtain the respective intermediates, 5,6 dichloro l6 methylenepregnane35,17a diol 20-one and 5-bromo6-chloro 16 methylenepregnane313,17a-di0l-20-0ne. Oxidation of the 3-hydroxy function with forexample chromic acid to the corresponding 3 keo 5,6 dihalogenopregnanefollowed by dehydrohalogenation with sodium acetate yields the B-isomer,which in this case is 6fl-chloro- 16-methylene-17a-hydroxyprogesterone.

A 6,8 fiuoro 16 lower alkylideneprogesterone of our invention issimilarly obtained by employing halogenating agents such as brominefluoride or chlorine fluoride with 16 methylene 5pregnene-3fi,17oc-diol-20- one. The necessary intermediates therebyformed, i.e. 5- bromo 6 fluoro 16-methylene-l7a-hydroxypregnane or 5chloro 6 fluoro-l6-methyleue-l7a-hydroxypregnane respectively, whensubjected to the series of reactions outlined in the preceding paragraphyields 6/3-flLIOIO-l6- methylene-17a-hydroxyprogesterone.

The 6B-chloro and 6fl-fluoro-16-lower alkylideneprogesterones preparedabove may be epimerized to the 60:- isomer by means of alcoholicsolutions of acids or bases yielding the corresponding6a-chloro-16-methylene-17uhydroxyprogesterone and6a-fluoro-l6-methylene-l7a-hydroxyprogesterone.

When utilizing reagents such as bromine fluoride, chlorine fluoride,chlorine or bromine chloride to prepare a 6-halogeno-l6-loweralkylidene-l7-acyloxprogesterone, it is preferred to carry through theabove-described reaction sequence on a compound having 17a-hydroxy groupand to esterify the resulting 6-halogeno-16-lower alkylidene 17oz.hydroxyprogesterone intermediate thereby formed by methods describedabove to obtain the desired 6-halogeno-l6-lower alkylidene 1700acyloxyprogesterone.

An alternate method of introducing a 6-chloro group into the moleculeutilizes as starting compounds the 16- lower alkylideneprogesterones ofour invention and reagents such as N-bromosuccinimide orN-chlorosuccinimide as the halogen donor. By this method 16-methylene-17u-acetoxy-2l-fiuoroprogesterone, for example, is converted to thecorresponding 3-enol-ether-3,5-diene by means of ethy1-o-formate in thepresence of an acid catalyst such as sulfuric acid. The3-eth0xy-l6-methylene-l7aacetoxy-Zl-fluoro-3,S-pregnadien-ZO-one thusprepared when reacted with N-chlorosuccinimide, for example, in thepresence of a solvent such as pyridine, with or without the aid of acatalyst such as p-toluenesulfuric acid, yields the 6,8-epimer,65-ch1oro-16-methylene-l7a-acetoxy 21- fiuoroprogesterone. Thecorresponding 6a-chloro-l6- methylene-l7 xacetoxy-2l-fiuoroprogesteroneis obtained from the aforementioned 6B-chloro compound by treatment withalcoholic hydrogen chloride. When N-bromosuccinimide is used in theforegoing procedure instead of N-chlorosuccinimide, the corresponding6-bromo compound of our invention is formed, i.e. 6,8-bromo-l6-methylene-l7a-acetoxy-21-fluoroprogesterone.

An alternate method of introducing a 6-fluoro group into the moleculeemploys perchloryl fluoride as the halogenating agent and as startingcompounds either a 3 enol-ether-3,5-diene exemplified by the abovedescribed 3- ethoxy-16-methylene-17 a-acetoxy-21-fluoro-3,5pregnadien-20-one, or a 3-enol-ester-3,5-diene such as3,17-diacetoxy-16-methylene-3,S-pregnadien-ZO-one. The latterintermediate is prepared from the corresponding 16-loweralkyl-16,17-oxidoprogesterone with an excess of acetic anhydride in thepresence of p-toluenesulfonic acid. Specifically, 3 17 -diacetoxy-16-methylene-3 ,5 -pregnadien-20- one reacted with perchloryl fluoride ina solvent such as pyridine yields6fi-fiuoro-16-methylene-17m-acetoxypr0- gesterone. The corresponding6a-fluoro-l6-methylene-17aacetoxyprogesterone is obtained from the6fl-fiuoro epimer by treatment with alcoholic hydrogen chloride.

Novel progesterones of Formula I possessing a hydrogen at -17 areconveniently prepared by reacting a 16- loweralkylidene-17a-acyloxprogesterone of the Formula I with an alkaline oran alkaline earth metal such as lithium or calcium in a basic mediumsuch as liquid ammonia or diethylamine, or by the action of zinc inaqueous ethanol. In the former procedure it is preferable that the3-keto group be protected with a ketal derivative such as the ethyleneketal. For example, 16-ethylidene- 17a-acet0xyprogesterone upontreatment with ethylene glycol is converted to the corresponding3-ethylene ketal derivative (i.e.3-ethylenedioxy-16-ethylidene-17a-acetoxy-S-pregnen-ZO-one) which whenreacted with calcium in liquid ammonia gives3-ethylenedioxy-l6-ethylidene-5- pregnen-20-one. Hydrolysis with a mildacid such as aqueous acetic regenerates the 3-ket0ne group to give16-ethylideneprogesterone.

The 6B-chloro and 6fi-fiuoro-16-lower alkylideneprogesterones depictedby Formula I are prepared by reacting a suitable halogenating agent witha 16-lower alkylidene-4, 9(11)-pregnadiene-3,20-dione or a 16-loweralkylidene-1, 4,9(11)-pregnatriene-3,20-dione or with a 6,17, or 21-monosubstituted, or a (6,17), (6,21), or (17,21)-disub stituted, or a6,17,21-trisubstituted-16-lower alkylidene-4,9(11)-pregnadiene-3,20-dione, the preferred substituents at the 6-carbonbeing fluorine, chlorine or methyl; and at the 2-carbon being fluorineor iodine. Our starting compounds are represented by M -unsaturatedprogesterones such as:

16-methylene-17a-hydroxy-4,9 1 1 -pregnadiene-3,20-

dione,

16-methylene-17u-acetoxy-4,9 11)-pregnadiene-3,20-

dione,

16-methylene-17a-caprooxy-4,9(1 1 -pregnadiene-3,20-

dione,

16-methylene-1,4,9(1 1 -pregnatrienel7a-ol-3-one,

6fi-fluoro-16-methylene-17a-hydroxy-4,9 11

pregnadiene-3,20-dione,

6a-fiuoro-16-methylene-17ot-hydroxy-4,9(11)- pregnadiene-3,20-dione,

6a-chloro-16-methylene-17oc-hyrdroxy-4,9( 1 1)- pregnadiene-3,20-dione,

6a-methyl-16-methylene-l7a-acetoxy-4,9 1 1 pregnadiene-3,20-dione,

and the like.

These starting materials necessarily possess a A -double bond which maybe introduced into the molecule either before or after the 16-methylenegroup is added to the progesterone nucleus. In either case the processof forming the double bond between C-9 and C-11 is identical, i.e. ahydroxyl group is introduced microbiologically at 011 with the aid of amicro organism, Curvularia lunata (N.R.R.L. 2380) or Rhizopus nigricans(A.T.C.C. 6227b) using procedures analogous to those in U.S. Pat No 2,658,- 023 and US. Pat. No. 2,602,769, respectively. When Curvularia Iunatais employed the 11,Bhydroxy steroid produced is dehydrated by a reagentsuch as methanesulfonyl chloride in the presence of pyridine orphosphorous oxychloride in pyridine to give the necessary intermediates.On the other hand, the action of Rhizopu s nigricans on a progesteronesuch as 6a-methyl-16-methylene-l7w hydroxyprogesterone yields thecorresponding lloc-hYdIOXY derivative, 6a-methyl-l1u,17a-dihydroxy-16methyleneprogesterone. Subsequent treatment with a sulfonylchloride suchas methanesulfonyl chloride or toluenesulfonyl chloride yields thecorresponding Ila-SlllfOIlflte which, when treated with a base such aspyridine or sodium acetate, gives the 9,11-dehydro intermediateexemplified by 6u-methyl-16-methylene-17u-hydroxy-4,9( 11pregnadiene-3,20-dione (6a-methyl-16-methylene-17a-hydr0xy 9 11)-dehydroprogesterone It is sometimes convenient to introduce the9,11-bond prior to the 16-lower alkylidene group such as, for example,when one has an 11 hydroxy compound intermediate available such as3,6,11a-dihydroxy-5,16-pregnadiene-ZO-one. Selective esterification ofthe 3-hydroxy group by means of pyridine and acetic anhydride yields3B-acetoxy-1 1a-hydroxy-5,16-pregnadiene-2O one which is then esterifiedat OH with p-toluenesulfonyl chloride as described above. The resultinglla-p-toluenesulfonate ester is dehydrated by means of sodium acetateand acetic acid to yield the 9,ll-dehydro intermediate; 5,9(11),l6-pregnatriene-3B-ol-20-one 3-acetate. A 16-lower alkyl group is thenintroduced according to the previously described procedures such as thatutilizing diazomethane followed by pyrolysis of the intermediary16,17-pyrazolino compound to yield 16-methyl-5,9(l1),16-pregnatrien3,8-0l-20-one 3 acetate. The 16,17 epoxide is conveniently obtained fromthe latter compound by hydrogen peroxide in alkali. The resultant16-lower alkyl- 16,17-epoxy intermediate, e.g. 16fi-methyl-16,17u-0Xid0-5,9(11)-pregnadien-3B-ol-20-one is converted by means of hydrogenbromide in acetic acid, for example, to the corresponding16-methylene-S,9( 11 )-pregnadiene-3,B,17adiol-20-one, a necessaryintermediate for producing dihalogen-lower alkylideneprogesterones ofour invention. Alternatively, the aforementioned 5,9(11)-pregnadiene,16fl-rnethyl 16oc,l7ot oxido-5,9(11)-pregnadien3,8-ol- 20-one may beconverted to the corresponding progesterone (A -3-keto) via an Oppenaueroxidation to give 165 methyl-16a,17a-oxido-9 1 1 )-dehydroprogesterone.Treatment of this 16-alkyl-16,l7-oxido intermediate with acetic acid andtrifluoroacetic acid according to our novel process yields thecorresponding l6-methylene-l7a-acetoxy-9 11 )-dehydro-progesterone.

In preparing 9,11-dihal0geno compounds which contain l7a-acyloxy groupsit is possible to introduce the A -bond into a 16-loweralkylidene-l7u-hydroxyprogesterone and then esterify the 17-hydroxylgroup either before or after introducing halogen at the 9 and 11-positions. For example, 911,1lfl-dichloro-16-methylene- 17oL-HCEEOXYPIOgEStEIOHe may be prepared by two routes. In one,16-methylene-17a-acetoxy-9 1 1 -dehydroprogesterone is prepared asdescribed in the preceding paragraph or, alternatively,16-methylene-17a-hydroxy-9(l1) dehydroprogesterone is converted by knowntechniques to the aforementioned 17-acetate ester which is thenchlorinated at C-9 and C-ll with, for example, lithium chloride,hydrogen chloride and N-chlorosuccinimide. Alternatively,16-methylene-l7u-hydroxy-9( 11 -dehydroprogesterone is chlorinated withchlorine and pyridine in carbon tetrachloride, for example, to give thenovel 11 3 dichloro l6-methylene-17a-hydroxyprogester0ne. Esterificationwith acetic acid and trifluoroacetic anhydride yields the desired 90c,llfi-dichloro-16-methylenel7a-acetoxyprogesterone.

In general, the 9u,11,B-dihalogeno compounds of the general formula areprepared from the above-mentioned 9(11) dehydro-lfi-loweralkylideneprogesterone intermediates by utilizing halogenating reagentsunder reaction conditions described in US. Pat. No. 2,894,963 and in thecopending applications of Robinson and Gould 13 et al., Ser. Nos.817,079 and 817,048, respectively, both filed June 1, 1959, now US.Pats. Nos. 3,009,933 and 3,049,554, respectively.

Our 9a-halogeno-11-oxygenated-16-lower alkylideneprogesterones are alsoconveniently prepared from the 16-1ower alkylidene-9 1 1)-dehydroprogesterone intermediates described heretofore. For example,6a-methyl-l6- methylene 17a-acetoxy-4,9( 11 )-pregnadiene-3,20-dionewhen reacted with N-bromoacetamide in aqueous dioxane in the presence ofperchloric acid according to known techniques yields the novel6a-methyl-9a-bromo-11 5,17- dihydroxy-l6-methyleneprogesteronel7-acetate.

Other 9zx-halogeno-11B-hydroxy-16-lower alkylideneprogesterones of ourinvention, i.e. the 9a-iodo, chloro and fiuoro are obtainable from thecorresponding 9 6,116- oxido-16-lower alkylideneprogesterones which, inturn, are derived from the 90: bromo-l1fi-hydroxy-16-loweralkylideneprogesterones by treatment with potassium acetate in ethanolor acetone. Addition of hydrogen chloride in chloroform or of hydrogenfluoride in chloroformtetrahydrofuran, or of hydrogen iodide in aceticacid to a 913,11,8-oxidoprogesterone yields the corresponding 90:-chloro-llB-hydroxy, 9a-fiuoro-11B-hydroxy, or Qoc-iOdO- llfi-hydroxy,respectively. Thus, 6cx-methyl-9a-brorno-1113,17a-dihydoxy-16-methyleneprogesterone 17 acetate is converted to6a-methyl-9,B,1lfl-oxido-l6-methylene- 17u-hydroxyprogesterone17-acetate. Addition of hydrogen fluoride to the oxide yields6u-rnethyl-9a-fiuoro-llflhydroxy-l6-methylene-l7a-acetoxyprogesterone ofour invention. By using hydrogen chloride or hydrogen iodide instead ofhydrogen fluoride with the aforementioned oxidoprogesterone, there isobtained 6a-methyl-9a-chloro- 11 p-hydroxy-l 6-methylene-17aacetoxyprogesterone and 6amethyl-9a-iodo-l1fl-hydroxy-1-6-methylene-17a-acetoxyprogesterone.

Esterification of the 9a-halogeno-11B-hydroxy-1 6-loweralkylideneprogesterones of our invention by means of, for example,acetic acid and trifluoroacetic anhydride yields the correspondingll-acylate, e.g. ll-acetate.

By utilizing the above procedure it is obvious that one needs but tochoose the appropriate A i -Hntermediate to obtain compounds such as9a-fiuoro-11 fi,17a-diacetoxy 16 methyleneprogesterone; 604,911difiuoro-16- fluoro l1B,17a-diacetoxy-16-irnethyleneprogesterone;6ozrnethyl-9a-fluoro-1 1,8,17u-diacetoXy-16-methylenel-dehydroprogesterone (6oc-I1'16tl1Y1-9ot-flllOIO-l16,170t diacetoxy-l6-rnethylene-1,4-pregnadiene-3,20-dione) 6-chloro- 9a fluoro1113,17a-diacetoXy-16-methylene-6-dehydroprogesterone(6-chloro-9oc-fluoro-l1}3,17a-diacetoxy 16- methylene-4,6-pregnadiene-3,20-dione) To obtain the ll-keto compounds of the general formulae theabove 9,11-halohydrins such as 9a-fiuoro-11B- hydroxy 17aacetoxy-I6-methyleneprogesterone may be oxidized with, for example,chromic acid to give as a representative example9a-fiuor0-1l-keto16-methylene-17a acetoxyprogesterone.

In preparing the l-dehydro analogs of the previously described 16-loweralkylideneprogesterones, ll-oxygenated-16-lower alkylideneprogesteronesand the 90,11fidihalogeno-16-lower alkylideneprogesterones of ourinvention, the A -bond may be introduced at various stages during thesynthesis of the compound and preferably in the later stages. Thus, a16-lower alkylidene-1-dehydroprogesterone such as 16 methylene17a-hydroxy-1,4- pregnadiene 3,20 dione,6a-chloro-16-methylene-17ahydroxy 1,4 pregnadiene-3,20-dione and6u-methyl-9afluoro 1113,17a-dihydroxy-16-methyleneprogesterone 17-acetate is prepared from the corresponding 16-l0weralkylideneprogesterones, e.g. 16 methylene-17a-hydroxyprogesterone, 6achloro 16-methy1ene-17-acetoxyprogesterone and 6a methyl9a-fluoro-1lB,17a-dihydroxy-16- methyleneprogesterone 17-acetate bymicrobiological dehydrogenation with an organism such as Corynebaczeriumsimplex (A.T.C.C. 6946) in a manner similar to that described in US.Pat. No. 2,837,464 or by chemical dehydrogenation through the use of areagent such as selenium dioxide. Similarly, 9a,11fl-dihalogeno-16-loweralkylidene-l-dehydroprogesterones of the general formula are obtainedfrom their corresponding 9u,11fl-dihalogeno- 16-loweralkylideneprogesterones, for example, 901,115- dichloro 21 fluoro16-methylene-17u-hydroxyprogesterone is converted to9a,l1;8-dichlor0-21-fluor0-16- methylene17a-hydroxy-1,4-pregnadiene-3,20-dione with the aid of Corynebacteriumsimplex. Alternatively, 11,8 dihalogeno 16-1oweralkylidene-l-dehydroprogesterones are obtained by first dehydrogenatinga 9(11)- dehydro 16-lower alkylideneprogesterone intermediate such as600 methyl-16-methylene-l7a-hydroxy-9(11)-dehydroprogesterone withCorynebacterium simplex to give 6a methyl16-methylene-17ahydroxy-1,4,9(l1)-pregnatriene-3,20-dione which uponchlorination by previously described methods yields 6-methyl-16-methy1ene-9u, 11B dichloro-lh-hydroxy-l-dehydroprogesterone.The 17a-hydropregnadiene thus produced may then be converted to the17-acyloxy compound by known esterification techniques to 6 methyl 16methylene-9a,11 8-di chloro-17a-acetoxy-l-dehydroprogesterone.

The 6-dehydro analogs of the 16-lower alkylideneprogesterones describedabove are obtained by subjecting the corresponding progesterone to theoxidizing action of chloranil. The novel 60: methyl16-methylene-17a-acetoxyprogesterone is transformed by means ofchloranil to the 6-dehydro analog,

6-methyl-16-methylene-17a-acetoxy-6-dehydroprogesterone(6-methyl-16-methylene-17-hydroxy-4,6- pregnadiene-3,20-dione17-acetate).

In like manner,

6a-fluoro-16-methy1ene-17a-acetoxyprogesterone,6a-fiuoro-16-methylene-17-acetoxyprogesterone,6a-chloro-21-fluoro-16-methylene-17a-acetoxyprogesterone, and6,21-difluoro-16-methylene-17a-acetoxyprogesterone are converted to6-chloro-16-methylene-17u-acetoxy- 6-dehydroprogesterone,6-fluoro-16-methylene-17a-acetoxy-6-dehydroprogesterone, and6-chloro-2l-fluoro-16-methylene-17u-acetoxy-6-dehydroprogesterone, and6,2l-difiuoro-16-methylene-17u-acetoxy-6-dehydroprogesterone.

The 16-lower alkylidene 1,6-bis-dehydrOprogesterones of our inventionare preferably prepared from the corresponding novel 16 loweralkylidene-6-dehydroprogesterones by known procedures utilizing seleniumdioxide. For example, 6 chloro16-methylene-17a-hydroxy-4,6-pregnadiene-3,20-dione 17-acetate reactedwith selenium dioxide and mercury in t-butyl alcohol and acetic acidyields 6 chloro 16 methylene-17u-hydroxy-1,4,6-pregnatriene 3,20 dione17 acetate (6 chloro-l6-methylene-17u-hydroxy-1,6-bisdehydroprogesterone 17-acetate).

The 19-nor analogs of our invention are obtained by pyrolysis of theheretofore described 16-lower alkylidenel-dehydroprogesterones. Forexample, 16-methylene-17ahydroxy l-dehydroprogesterone(16-methylene-17a-hydroxy-l,4-pregnadiene-3,ZO-dione) is pyrolyzedeither in the solid state or in an inert solvent to efiect eliminationof the 19-methy1 and concomitant aromatization of ring- A. The 3,17ocdihydroxy-16-methylene-17fl-acetyl-1,3,S (10)-estratriene thus obtainedis converted to its 3-methyl ether with dimethylsulfate in alkalinemethanol. The resultant 3 methoxy16-methylene-17a-hydroxy-17/3-acetyl-1,3,5(10)-estratriene is convertedby means of ethylene glycol to the corresponding ZO-ethylene ketal whichis reacted with liquid ammonia and lithium in the presence of a protondonor (such as ethanol) and subsequently treated with a reagent such asrnethanolic hydrochloric acid to give 16 methylene-17a-hydroxy-19-norprogesterone. In the last step of the aforementioned procedure, ifone employs oxalic acid instead of hydrochloric acid there is obtainedan intermediary compound, 16methylene-17a-hydroxy-19-nor-S(10)-pregnene-3,20- dione which uponstronger acid treatment is converted to the above 19 norprogesterone,16-methylene-17whydroxy 19-nor-4-pregnene-3,20-dione. Esterificationwith trifluoroacetic anhydride and acetic acid yields 16-methylenel7a-acetoxy-19-norprogesterone. By substituting other lower alkanoicacids such as caproic or t-butylacetic for acetic acid in theesterification procedure, one obtains the corresponding 17-loweralkanoates, i.e. 16- methylene l7a-hydroxy-19-norprogester0ne17-caproate and 16-methylene-17a-hydroxy-19-norprogesterone17-tbutylacetate.

The following compounds may be obtained from 16-methylene-17u-hydroxy-19-n0rprogesterone (prepared as above) byutilizing a series of reactions similar to those outlined heretofore forthe corresponding 19-methyl analogs: 6ozmethyl-l6-methylene-17a-acetoxy-19-norprogesterone, 60cfluorO-l6-methylen -17a-hydroxy-l9-norprogesterone, 60c fiuoro16-methylene-17a-acetoxy-19- norprogesterone, 60:,21 difluoro16-methylene-l7a-hydroxy 19 norprogesterone, and6a,21-difiuoro-16-methylene-17a-acetoxy-l9-norprogesterone. The 2l-iodoanalogs of the above compounds as well as the 9,11-dihalogeno(9a,11;8-dichloro, 9a-chloro-11p-fluoro, and the like) derivatives arealso obtained by the procedures described above.

Compounds other than the above described16-loweralkylidene-l-dehydroprogesterones which may be subjected topyrolysis include the llu-hydroxylated 16-alkylidene progesterones ofour invention, which are conveniently prepared from the correspondingll-desoxyprogesterones of our invention by treatment with Rhizopusnigricans. For example, 6a-fluoro-11a,17u-dihydroxy-16-methyleneprogesterone (obtained by the action of Rhizopus nigricans on6a-fiuoro-16-methylene-17a-hydroxyprogesterone) may be transformed bymicrobiological dehydrogenation by means of Corynebacterium simplex tothe l-dehydro analog, Got-fllJOIO-l10:,170z-dlhYdIOXY-16- methylene 1,4pregnadiene 3,20-dione, which is transformed via pyrolysis andsubsequent chemical transformation as described above into6a-fluoro-11a,17a-dihydroxy- 16-methylene19-nor-progesterone. By formingan 11- sulfonate acid ester such as ll-p-toluenesulfonate followed byreaction with sodium acetate and acetic acid according to proceduresdescribed heretofore, there is obtained 60: fluoro16-methylene-17a-hydroxy-9(11)-dehydro-19- nor-progesterone, a usefulintermediate in the preparation of 9a,11/3-dihalogeno derivatives suchas 6oc-fil1010 9a,11fl-dichloro 16 methylene 17ahydroxy-19-norprogesterone, 611,21diflllOI'O-9ot,11/3-diCl1lOIO-l6-Ill6thYlene-17u-hydroxy-19-nor-progesterone,and the like.

As illustrated in great detail hereinabove, the 16-1oweralkylidene-17a-hydroxypregnanes of the composition aspect of thisinvention which are derived from the process aspect of this inventionare useful for the preparation of therapeutically active l6-alkylidenesteroids. The novel compounds arising from our process also serve asvaluable precursors for 16-alkyl steroids. Depending upon the conditionsemployed, it is possible to obtain either the a or 18 configuration ofthe 16-a1kyl group. Thus, upon hydrogenating under acidic conditions asin acetic acid and employing palladium on carbon as the catalyst, thereis obtained from a l-methylene compound the corresponding 16a-methylsteroid, Whereas upon hydrogenation under basic or neutral conditions asin ethyl acetate, and in ethyl acetate containing triethylamine, andemploying palladium on carbon, there is formed predominantly the16/3-alkyl isomer. Thus, there can be obtained from16-methylene-pregnane-3a,17a-diol-20-one 3-acetate upon reduction asdescribed above the compound 16:):- methyl-pregnane-3a,l7a-diol-20-oneS-acetate which can be converted to dexamethasone by transformationswhich have been applied to analogous compounds which includeintroduction of a 21-hydroxy group by bromination followed byacetoxylation at C-2l, then by oxidation with chromium trioxide inacetone-sulfuric acid, to the 3-keto analog, dibromination at C-2 andC-4 followed by dihydrobromination with dimethylformamide, yielding16ozmethy -1,4-pregnadiene-17a,21-diol-3,20-dione 21-acetate. Thiscompound, in the form of the 21-free alcohol, is lla-hydroxylatedmicrobiologically in known manner and then converted via the 9,11-eneand 9,11-oxide, followed by treatment with hydrogen fluoride, todexarnethasone.

The following examples are illustrative of the procedures employed inpreparing the compounds of this invention but are not to be construed aslimiting the scope thereof, the scope of our invention being limitedonly by the appended claims.

EXAMPLE 1 16,8-methyl-16a,l7u-oxido-5-pregnen-3fl-ol-ZO-one To asolution of 32 ml. of 50% aqueous sodium hydroxide in ml. of water isadded a solution of 164 g. of 16-methyl-5,l6-pregnadiene-3B-ol-ZO-one in500 ml. of chloroform and 1200 ml. of methanol. The mixture is cooled tobelow 25 C. and then there is added with stirring 225 ml. of 35%hydrogen peroxide. Stirring is continued for 48 hours and the mixture isacidified with acetic acid. A saturated solution of sodium sulfide isadded until any excess peroxide is destroyed as determined by theiodide-starch test. The mixture is then steam distilled and the residuefiltered. The solid is recrystallized from acetone to give16/3-methyl-l6u,17a-oxido-5-pregnen-3fl-ol-20-one, M.P. 188 C. [a] 20(1% in dioxane).

By employing the above procedure and utilizing as starting compounds,16-rnethyl-16-pregnen-3u-ol-20-one and16-methyl-16-allopregnen-3B-ol-20-one (which can be prepared from theappropriate starting compounds pursuant to the procedures described inBelgian Pat. No. 577,030 (published September 1959), in I. Am. Chem.Soc. (Slates et al.) 81, 5472 (September 1959) and in J. Am. Chem. Soc.(Mueller and Riegel) 76, 3086 (1954)) there are prepared respectively,the compounds 1 6pmethyl l6oc,17oc oxido-pregnan-3a-ol-20-one and 165-methyl-16a,17u-oxidoallopregnan-3 5-ol-20-one.

EXAMPLE 2 16fl-methy1-16u,17a-oxido-5-pregnen-3B-ol-20-one 3-acetate Toa solution of 167 g. of 16,8-methyl-16,17-oxido-5- pregnen-3fi-ol-20-onein 500 ml. of dry pyridine is added 167 ml. of acetic anhydride. Themixture is then heated at 60 C. for 10 hours, cooled to room temperatureand precipitated by the addition of 3000 ml. of ice water. The crudeproduct is collected by filtration, washed well with ice water untilfree of pyridine, dried and crystallized from acetone to give16,8-methyl-l6u,17a-oxido-5-pregnen-3B-ol-20-one 3-acetate, M.P. -182"C. 16.7 (1%, dioxane).

In a similar fashion by employing16fi-methy1-16a,17uoxidopregnan-3a-ol-20-one and16fi-methyl-16u,17a-oxidoallopregnan-3fl-ol-ZO-one, there are preparedrespectively 16p methyl 16a,17a-oxidopregnan-3a-ol-20-one 3-acetate and16B-methyl-16a,17a-oxidoallopregnan-Lifl-ol- 20-one 3-acetate.

EXAMPLE 3 16-methylene-S-pregnene-Bfi,17rx-diol-20-one 3-acetate To asolution of 110 g. of 16fl-methyl-16u,17ot-oxido-5-pregnen-3fl-ol-20-one 3-acetate in 2420 ml. of acetic acid is added2.42 g. of hydrogen bromide. The mixture is agitated for 5 minutes at 30C. and then filtered. The solid thus collected is washed with 80% aceticacid and dried. The mother liquor is poured into 10 parts of water 17and filtered, washing the solid with ice water until neutral. This solidis then combined with the solid obtained above and recrystallized fromacetone to yield 16-methylene-5- pregnene-3B,17a-diol-20-one 3-acetate,M.P. 200 C. [111 109.5 (1%, dioxane).

In a similar manner, by subjecting 16,B-methyl-16a,17xoxidopregnan-3a-ol-ZO-one 3-acetate and 16fi-methyl-16a,17a-oxidoallopregnan-3fi-ol-20-one B-acetate to the procedure recitedherein, there are prepared respectively 16-methylenepregnane-3a,17a-diol-20-one 3-acetate and 16-methyleneallopregnane-3,8,17a-diol-20-one 3-acetate.

Likewise, by employing 16,8-methyl-16a,17a-oxido-5-pregnen-3fl-ol-20-one as the starting material in the procedure of thisexample there is obtained 16-methylene-5- pregnene-3/3,17a-diol-20-one.

Alternatively, other acids may be substituted for hydrogen bromide.Thus, for example, equivalent amounts of hydrogen chloride,trifluoroacetic acid, or p-toluenesulfonic acid may be employed withsubstantially the same results.

EXAMPLE 4 16-ethylidene-5-pregnene-3/3,17a-diol-20-one 3-acetate Byutilizing 16-ethyl-5,16-pregnadien-3fl-ol-20-one as the startingcompound in the procedure of Example 1, there is obtained16fl-ethyl-16a,17u-oxido-5-pregnen-3flol-20-one which, when reacted withacetic anhydride in pyridine according to the procedure of Example 2, isesterified at O3 to give16,8-ethyl-16a,17a-oxido-5-pregnen-3fl-ol-20-one 3-acetate. Reaction ofthe latter compound (i.e. the 3-acetate) with hydrogen bromide in aceticacid in a manner similar to that described in Example 3 yields16-ethylidene-5-pregnene-3/i,17a-diol-20-one 3-acetate.

It will be evident that the 3-esters described above can be hydrolyzedin known manner, as with sodium carbonate or sodium hydroxide, to obtainthe corresponding 3- hydroxy compound, e.g.16-ethylidene-5-pregnene-318,17adiol-20-one. Similarly, the 3-acetateesters prepared in Example 3 are hydrolyzed to obtain16-methylene-5-pregnene-3B,17a-diol-20-one,16-methylene-pregnane-3u,17adiol-20-one and16-methylene-5aregnane-SB,17a-diol-20- one, respectively.

By employing as starting compound, the 3-ketoand the 3-keto-4-pregneneanalogs of the starting compounds of Examples 1-4, there is obtained thecorresponding 3- keto-16-alkylidene-17a-hydroxyand the3-keto-16-alkylidene-l7a-hydroxy-4-pregnene analogs of the compoundsprepared in each of Examples 1-4. For example, reaction of16-methyl-4,l6-pregnadiene-3,20-di0ne and 16-ethyl-4,16-pregnadiene-3,20-dione with alkaline hydrogen peroxide according tothe procedure of Example 1 gives respectively, l63-methyl-l6a,17a-oxidoprogesterone and16fl-ethyl-16a,17a-oxidoprogesterone. Reaction of each of the foregoingwith hydrogen bromide in acetic acid according to the procedure ofExample 3 yields respectively, 16-methylene-4-pregnene-l7a-ol-3,20-dioneand 16-ethylidene-4-pregnen-17a-ol-3,20-dione. An example of the use ofa saturated 3-keto starting compound follows:

EXAMPLE 16-methylene-17a-hydroxypregnane-3,20-dione (A)1GB-methyl-l6a,17a-oxidopregnan-3fl-ol-20-one. To a solution of 60 ml.of 50% aqueous sodium hydroxide in 220 ml. of water is added a solutionof 335 g. of 16- methyl-16-pregnen-3/3-ol-20-one in 900 ml. ofchloroform and 2200 ml. of methanol. The mixture is cooled to below 25C. and then there is added with stirring 425 ml. of 35% hydrogenperoxide. Stirring is continued for 48 hours and the mixture isacidified with acetic acid. A saturated solution of sodium sulfite isadded until any excess peroxide is destroyed as determined by theiodidestarch test. The mixture is then steam distilled and the 18residue filtered. The solid is recrystallized from acetone to give16fi-methyl-16a,17a-oxidopregnan-3fl-ol-20-one.

(B) 16 8-methyl16a,17a-oxidopregnane-3,20-dione. 10 grams of16,8-methyl-16a,l7a-oxidopregnan-3p-ol-20- one are dissolved in 750 ml.of toluene. About ml. of toluene is distilled, then ml. of freshlydistilled cyclohexanone is added to the solution, followed by thedropwise addition over a five minute period of a solution of 5 g. ofaluminum isopropoxide in dry toluene. The solution is refluxed for onehour under a Dean-Stark trap. 60 ml. of water is added cautiously andthen the water is removed by azeotropic distillation. The solution iscooled, filtered and the filtrate is steam distilled. The suspensionleft'after steam distillation is filtered. The solid residue is washedwith water, dried and crystallized from isopropyl ether to give16,8-methyl-16a,17a-oxidopregnane-3,20- dione.

(C) 16-methylene-17a-hydroxypregnane-3,20-dione.-- A solution of 14 g.of 16fi-methyl-16u,17a-oxidopregnane- 3,20-dione in 350 ml. of aceticacid is warmed to 35 C. A 10% solution of hydrobromic acid in aceticacid (3.5 ml.) is added. The reaction mixture is maintained atapproximately 3545 C. for 20 minutes, then is diluted with 4 l. ofwater. A precipitate results which is filtered, washed with water, driedat 60 C. and crystallized from acetone to give16-methylene-17u-hydroxypregnane-3,20- dione.

The analogous l-pregnene compounds yield, for example, the1-pregnene-3X-16,17oxido-16Balkyl-20-ones which in turn give thel-pregnene-SX-16-alkylidene-20- ones, X being keto, hydroxyl or acyl. Inthe case of the 3-keto-pregnenes, when utilized as intermediates in thepreparation of 16-lower-alkyl-17a-hydroxy compounds, we prefer toprotect the keto group as by conversion to an ethylene glycol ketalgroup prior to reduction of the 16-alkylidene group to alkyl.

EXAMPLE 6 16-methylene-17a-hydroxyprogesterone (A) l6 3-methyl 16a,17aoxidoprogesterone.25 grams of l68-methyl-16a,17a-oxido5-pregnen-3/3-ol-20- one are dissolved in 1725 ml.of toluene. About 175 ml. of toluene is distilled, then 375 ml. offreshly distilled cyclohexanone is added to the solution, followed bythe dropwise addition over a five minute period of a solution of 12.5 g.of aluminum isopropoxide in dry toluene. The solution is refluxed forone hour under a Dean-Stark trap. 60 ml. of water is added cautiouslyand then the water is azeotroped off. The solution is cooled, filteredand the filtrate steam distilled. The suspension left after steamdistillation is filtered. The solid residue is washed with water, driedand crystallized from isopropyl ether to give16fl-methyl-16a,17a-oxidoprogesterone, XETOH 240 mu. (6 16,760); M.P.163 C.; [a] +118.0 (dioxane).

(B) 16-methylene-17a-hydroxyprogesterone.A solution of 6.93 g. of16B-methyl-16a,17a-oxidoprogesterone in ml. of acetic acid is warmed to35 C. A 10% solution of hydrobromic acid in acetic acid (1.7 ml.) isadded. The reaction mixture is maintained at approxi mately 3545 C. for20 minutes, then is diluted with 2 l. of Water. A precipitate resultswhich is filtered, washed with water, dried at 60 C. and crystallizedfrom acetone to give 16-methylene-17a-hydroxyprogesterone, AETOH 240 m(6 16,600); M.P. 219-222" C. [0411) +17 (dioxane).

EXAMPLE 7 16-methylene-17u-hydroxyprogesterone 17-acetate One gram of16-methylene-17a-hydroxyprogesterone is dissolved in 10 ml. of aceticacid. Argon gas is bubbled through the acetic acid solution and then,under anhydrous conditions, 1.99 ml. of trifluoroacetic anhydride isadded. The solution is heated at 80-95 C. for 55 minutes, then is pouredinto ice-water. The resultant mixture is extracted with methylenechloride. The organic extracts are combined and, in turn, are extractedwith 3% aqueous potassium carbonate and finally with water. Themethylene chloride solution is dried over magnesium sulfate, filteredand evaporated to a residue which, upon trituration withacetone-isopropyl ether yields a solid, which is filtered and dried togive 16-methylene-17a-hydroxyprogesterone 17-acetate, NETOH 240 ma (617,300); M.P. 227227.5 C.; [M 51.8 (dioxane).

In the above procedure, by substituting other lower alkanoic acids suchas caproic and propionic acids for acetic acid, there is obtained thecorresponding 17-lower alkanoate ester, i.e. the 17-caproate and17-propionate, respectively of 16-methylene-l7u-hydroxyprogesterone.

Alternatively, the compound of this example is prepared in the followingmanner. 8.8 grams of 16,8-methyl-16a, 17a-oxidoprogesterone aredissolved in 88 ml. of acetic acid. Argon gas is gently bubbled throughthe solution to displace the air, then 17.5 ml. of trifluoroaceticanhydride is added. The resulting dark brown solution is warmed at 3040C. for about one hour under anhydrous conditions. The reaction mixtureis then diluted with water and extracted with methylene chloride. Theextracts are combined, washed with 3% aqueous sodium carbonate, thenwith water and is evaporated to a residue which is crystallized fromacetone-ether to give 16-methylene-17ahydroxyprogesterone 17-acetate.

EXAMPLE 8 16-methylene-17a-hydroxy-1,4-pregnadiene- 3,20-dione17-acetate A solution of 1 g. of yeast extract (Difco) in 1 liter of tapwater, the pH of which is adjusted to 6.9, is distributed among ten 300ml. Erlenmeyer flasks and to each flask is added a loopful, 2 ml., ofCorynebacterium simplex (A.T.C.C. 6946). The resulting suspensions areincubated at 30 C. on a shaking machine for 18 hours. One-half gram of16-methylene-17u-hydroxyprogesterone is dissolved in 20 ml. of acetoneand the resulting solution is distributed equally among the ten flaskscontaining the 18 hours growth of Corynebacterium simplex. The culturecontaining the progesterone is then incubated at 30 C. for 24 hours. Atthe end of 24 hours, the contents of the flasks are combined andextracted with a total of 3 liters of chloroform. The crude chloroformextract from the transformation is then concentrated to a residue whichis crystallized from acetonehexane to give 16-methylene-17a-hydroxy-1,4-pregnadiene-3,20-dione.

In the manner described in Example 7, 1 g. of 16-methylene-17a-hydroxy-1,4-pregnadiene-3,20-dione is reacted with aceticacid and trifiuoroacetic anhydride and purified in the described mannerto give 16-methylene- 17a-hydroxy-1,4-pregnadiene-3,20-dione 17-acetate.

EXAMPLE 9 6m-methyl-16-methylene-17a-hydroxyprogesterone (A) 6-methyl-16,17 -pyrazolino-5-pregnen-35-ol-20-one 3-acetate.--A solution of 3.5g. of 6-methyl-5,l6-pregnadien-3fi-ol-20-one 3-acetate in 5 ml. ofmethylene chloride is added to a solution of approximately 1 g. ofdiazomethane in 65 ml. of ether which had been cooled to approximately10 C. The mixture is kept at C. for hours, then allowed to warm up toroom temperature. The excess diazomethane is displaced with a nitrogenstream and the reaction solution is evaporated to a residue which iscrystallized from acetone-ether to give6-methyl-16,17-pyrazolino-5-pregnen- 3/3 -ol-20-one 3-acetate.

(B) 6,16-dimethyl-5,16-pregnadien-35-ol-20-one 3-acetate.-The16,17-pyrazolino prepared in Example 9A is heated under reduced pressureat approximately 10 mm. vacuum until liquifaction occurs. Thetemperature and pressure is maintained until the evolution of nitrogenhas ceased. The residual oil is then cooled to room temperature andcrystallized from ether to give 6,16-dimethyl-5, l6-pregnadien-33-ol-20-one 3-acetate.

(C) 6,16fi-dimethyl-16u,17a-oxido- 5 -pregnen-3/3-ol-20- one.To asolution of 1.5 g. of 6,16-dimethyl-5,16-pregnadien-3B-ol-20-one3-acetate in ml. of methanol at approximately 15 C. is added 3 ml. of 4N sodium hydroxide followed by 6 ml. of 30% hydrogen peroxide solution.The mixture is allowed to remain at approximately 5 C. for 18 hours. Thereaction solution is poured into 500 ml. of water and the resultingprecipitate is filtered, dried and crystallized from acetone-hexane togive 6,16/3-dimethyl 16a,17oc oxido-S-pregnen-318-01-20- one.

(D) 6a,16fl-dimethyl-16a,17a-oxidoprogesterone. 6, 1613 dimethyl1611,1704 oxido-5-pregnen-3fl-ol-20-one (0.5 g.) is dissolved in 35 ml.of toluene. After collecting by distillation approximately 4 ml. oftoluene, 7.5 ml. of freshly distilled cyclohexanone is added, followedby the dropwise addition of a solution of 0.25 g. of aluminumisopropoxide in dry toluene. The solution is refluxed for 1 hour under aDean-Stark trap, then 1.2 ml. of water is added cautiously, and then thewater azeotroped off. The solution is cooled, filtered and the tolueneand cyclohexanone are removed by steam distillation. The resulting solidis filtered, washed with water, dried and crystallized from isopropylether to give 6a,16,8-dimethyl-16a,17a-oxidoprogesterone.

(E) 6oz methyl 16 methylene 17oz hydroxyprogesterone.ln a manner similarto that described in Example 3,6a,16fi-dimethyl-16u,17a-oxidoprogesterone is reacted with a 10%solution of hydrobromic acid in acetic acid and the resultant productisolated and purified as described to give6a-methy1-16-rnethylene-17a-hydroxy progesterone.

The 17-acetate ester of the compound of this example is prepared from6a,l6fl-dimethyl-160:,17oc-OXiClOPIO- gesterone by the alternateprocedure of Example 7 to give 6a-methyl-16 methylene-17ahydroxyprogesterone 17-acetate.

EXAMPLE 10 16-methyl-5 ,9 1 1 ,16-pregnatrien-3fl-ol-20-one 3-acetate(A) 318,110: dihydroxy 5,16 pregnadien 20 one 3-acetate.To a solution of1.1 g. of 3p,11a-dihydroxy- 5,16-pregnadien-20-one in 10 ml. of drypyridine is added 0.33 g. of acetic anhydride and the reaction mixtureis allowed to remain at room temperature for 3 hours. Water is added anda precipitate results which is filtered, dried, and then crystallizedfrom methanol to give 3/3,l1ocdi hydroxy-5,16-pregnadien-20-one3-acetate.

(B) 35,110; dihydroxy 5,16 pregnadien 20 one 3-acetatel1-p-toluenesulfonate.A solution of 2.5 g. of3fl,11a-dihydroxy-S,16-pregnadien-20-one 3-acetate in 10 ml. ofchloroform and 14 ml. of dry pyridine is chilled in an ice-bath, then2.5 g. of p-toluene-sulfonyl chloride is added in small portions. Thereaction mixture is stirred in the cold for 80 minutes, then allowed towarm to and remain at room temperature for 18 hours. The reactionmixture is then poured ice-water, stirred and extracted with chloroform.The organic extracts are combined, washed with water, dried overmagnesium sulfate, filtered and concentrated in vacuo to a residue whichis crystallized from methanol to give3,8,11a-dihydroxy5,16-pregnadien-ZO-one 3-acetate ll-p-toluenesulfonate.

(C) 3/3 hydroxy 5,9(11),16 pregnatrien 20 one 3-acetate.To a solution of1.9 g. of anhydrous sodium acetate in 20 ml. of acetic acid, at aboutC., is added 1.25 g. of 3,8,11ot-dihydroxy-5,l6-pregnadien-20- one3-acetate ll-p-toluene sulfonate. The solution is refiuxed for 40minutes, then chilled in ice, and diluted with cold water. The resultantprecipitate is filtered, washed with water, dried and crystallized fromacetone-hexane to give 3/3-hydroxy-5,9(11),16-pregnatrien-20-one3-acetate.

(D) 38 hydroxy 16,17 pyrazolino 5,9(11) pregnadien-ZO-one 3acetate.lnthe manner of Example 9A, 3/3-hydroxy-5,9(1l),16-pregnatrien-20-one3-acetate is reacted with diazomethane. The resultant product isisolated in the described manner and crystallized from acetonehexane togive 3fi-hydroxy-16,17-pyrazolino-5,9(11)-pregnadien-20-one 3-acetate.

(E) 3 3 hydroxy 16 methyl 5,9(11),16 pregnatrien-20-one 3-acetate.-The16,17-pyrazolino-5,9(11)- pregnadiene of above Example 10D is heatedunder reduced pressure in the manner of Example 9B. The resultantproduct is isolated in the described manner and crystallized from ethylether to give 3fi-hydroxy-16-methyl- 5,9(11),16-pregnatrien-20-one3-acetate.

EXAMPLE 1 1 3 f3, 17a-dihydroxy- 1 6-methylene-5 ,9 l 1 -pre gnadien-20-one (A) 35 hydroxy 16 8 methyl 1604,1711: oxido- 5,9(1l) pregnadien20 one-35 hydroxy 16- methyl-5,9(11),16-pregnatrien-20-one 3-acetate isreacted with alkaline hydrogen peroxide in the manner of Example 9C andthe resultant product isolated in the described manner and crystallizedfrom acetone-hexane to give 3B-hydroxy-l6 3 methyl-16a,17aoxido-5,9(l1)- pregnadien-ZO-one.

(B) 35,17a dihydroxy 16 methylene 5,9(11)- pregnadien-ZO-one-In themanner of Example 3, 36- hydroxy 166 methyl 16a,l7oc oxido 5,9(11)-pregnadien-ZO-one is reacted with acetic acid and hydrobromic acid. Theresultant product is isolated as described and crystallized from acetoneto give 3B,17u-dihydroxy- 16-methylene-5 ,9 l 1 )-pregnadien-20-one.

EXAMPLE 12 16-methy1ene-17a-hydroxy-4,9 11 )-pregnadien- 3,20-dione andthe 17-acetate ester (A) 166 methyl 16,17a oxido 4,9(11) pregnadiene3,20 dione.3B hydroxy 16p methyl-16a,17u-oxido-5,9(11)-pregnadien-20"one is reacted with aluminumisopropoxide and cyclohexanone in toluene in the manner of Example 6A.The resultant product is isolated as described and crystallized fromether to give 16(3- methyl-16a,17a-oxido-4,9'( 11 )-p1'egnadiene-3,2-dione.

(B) 16 methylene 17a hydroxy 4,9(11) pregnadiene-3,20-dione.-The16OL,17OL-OXidO-5,9(1 1 -pregnadiene of Example 12A is reacted withacetic acid and hydrobromic acid in the manner of Example 3. Theresultant product is isolated in the described manner and crystallizedfrom acetone-hexane to give 16-methylene-17a-hydroxyl-4,9(11)-pregnadiene-3,20-dione.

(C) 16 methylene 17a hydroxy 4,9(11) pregnadiene 3,20 dione 17acetate.In a manner similar to that of Example 7, 1 g. of16-methylene-17a-hydroxy- 4,9(11)-pregnadiene-3,20-dione is reacted withacetic acid and trifiuoroacetic anhydride to give 170: hydroxy 16-methylene-4,9( 1 1 )-pregnadiene-3,20-dione 17-acetate.

EXAMPLE 13 6a-chloro-16-methylene-17a-hydroxyprogesterone and the 9 1 1-dehydro analog (A) 36,170 dihydroxy 16-methylene-5-pregnen-20- one.Onegram of 35,170: dihydroxy-16-methylene-5- pregnen-20-one 3-acetate isdissolved in 25 ml. of methanol and ml. of water containing 0.2 g. ofpotassium bicarbonate. This solution is refluxed for /2 hour, thenconcentrated in vacuo. Water is added to the residue and the resultantprecipitate is filtered, dried and crystallized from acetone-hexane togive 3fi,l7u-dihydroxy-l6-methylene-5- pregnen-ZO-one.

(B) 313,170; dihydroxy 5,6 dichloro-16-methylenepregnan-ZO-one and the9(11)-dehydro analog thereof. A solution containing 5.8 g. of 313,17ocdihydroxy 16- methylene-S-pregnen-20-one and 3.5 ml. of pyridine in 200ml. of chloroform is cooled to 25 C. To this stirred solution is addeddropwise over a 15-minute period 1.16 g.

of chlorine contained in 20 ml. of carbon tetrachloride. With continuedstirring, the reaction solution is allowed to warm to approximately 15C., then washed successively with dilute hydrochloric acid, water,aqueous sodium thiosulfate, and water. The organic phase is dried overmagnesium sulfate, filtered, and the filtrate evaporated to a residuewhich is treated with methanol to give 35,17adihydroxy 5,6dichloro-16-methylenepregnan-ZO-one.

In similar manner, react 3,8,17adihydroxy-16-methylene-5,9(11)-pregnadien-20-one with chlorine in carbontetrachloride and pyridine in the manner described above. Isolate theresultant product in the manner described and purify by crystallizationfrdm acetone to give 3/3,17u-dihydroxy-5,6-hichloro-l6-methylene-9( 11)-pregnen-20-one.

(C) 5,6-dichloro 16 methylene 17a-hydroxypregnane-3,20-dione and the9(11) dehydro analog.To a stirred solution of 1.3 g.of3/3,17a-dihydroxy-5,6-dichloro- 16-methylenepregnan-20-one in 3.0 ml.of acetic acid and 0.4 ml. of water at 10 C. is added over a 10-minuteperiod a solution containing 0.35 g. of chromium trioxide in 1 ml. ofacetic acid and 1 ml. water, followed by 0.012 ml. of concentratedsulfuric acid. The reaction mixture is stirred for 30 minutes, thendiluted with water and extracted with chloroform. The combinedchloroform extracts are washed with water, aqueous sodium bicarbonateand finally with water. The chloroform solution is dried and evaporatedto a residue substantially of 5,6-dichloro- 16methylene-17u-hydroxypregnane-3,ZO-dione which is used without furtherpurification in the following reaction 13D.

In a manner similar to that described hereinabove, react 3,8,17ocdihydroxy-5,6-dichloro-16-methylene-9(1l)- pregnen-ZO-one with chromiumtrioxide in acetic acid and in the presence of sulfuric acid. Isolatethe resultant prod not as described to give5,6-dichloro-l6-methylene-17ahydroxy-9(11)-pregnene-3,20-dione which isused without further purification in the following procedure 13E.

(D) 65 chloro 16 methylene 17a-hydroxyprogesterone and the 9(11)-dehydroanalog-The 5,6-dichloro- 3-keto-pregnane of Example 13C (1.9 g.) isrefluxed in 85.5 ml. ethanol in the presence of 2.05 g. of anhydroussodium acetate for 2 hours. The reaction solution is evaporated to aresidue to which water is added. A solid separates which is filtered,dried over magnesium sulfate, and crystallized from acetone-hexane togive 6B-chloro-16- methylene-17a-hydroxyprogesterone.

In a similar manner,5,6-dichloro-l6-methylene-l7a-hydroxy-9(11)-pregnene-3,20-dione isreacted with sodium acetate in ethanol. The resultant product isisolated as described and crystallized from ethyl acetate-hexane to give65 chloro-16-methylene-17a-hydroxy-4,9(11)-pregnadiene-3,20-dione.

(E) 60c chloro 16-methylene-17a-hydroxyprogesterone and the9(11)-dehydro analog.6B-chloro-16-methylene-17a-hydroxyprogesterone mg.)is dissolved in 30 ml. of chloroform and the solution is cooled to 10 C.A stream of anhydrous hydrogen chloride is bubbled through the solutionduring a period of 2 hours while maintaining the temperature at 10 C.The chloroform solution is washed with sodium bicarbonate solution andwater, then dried and evaporated to a residue. Crystallization fromacetonehexane gives 6oc-Chl010-l6-m6thYl6I16-l7ahydroxyprogesterone.

Similarly, the 6,8-chloro-4,9(11)-pregnadiene of Example 13D is reactedwith anhydrous hydrogen chloride in chloroform. The resultant product isisolated as described and crystallized from acetone-hexane to give6a-chloro- 16 methylene 17a-hydroxy-4,9(11)-pregnadiene-3,20- dione.

(F) 6a chloro-16-methylene-17u-hydroxyprogesterone 17-acetate and the9(11)-dehydro analog.In a manner similar to that described in Example 7,the 17a-hydroxyprogesterones prepared in Example 13B are reacted withacetic acid and trifluoroacetic anhydride to give 6oc-Cl'1l01'0- 16methylene-17a-hydroxyprogesterone 17-acetate and 23 6oz chloro-l6-methylene-17a-hydroxy-9 1 1 -dehydroprogesterone 17-acetate,respectively.

EXAMPLE 14 9a,l 1 p-dichloro- 1 6-methylene-17a-hydroxyprogesterone17-acetate and the 6-chloro-derivative (A) To 10 g. of the17a-hydroxy-l6-methylene-4,9(11)- pregnadiene-3,20-dione 17-acetatedissolved in 35 ml. of carbon tetrachloride at 20 C., is added 2.1 ml.chlorine gas in carbon tetrachloride 111 mg. Cl /ml.) and 0.75 ml. ofpyridine. The mixture is stirred at 20 C. for 20 minutes, then allowedto warm to room temperature over 40 minutes. The solution is filteredand the filtrate concentrated in vacuo to a residue which is trituratedwith ether. A solid results which is crystallized from acetonehexane togive 90,1lfi-dichloro-16-methylene-17u-hydroxyprogesterone 17-acetate.

Alternatively, 9a,l1,B dichloro-l6-methylene-l7ot-acetoxyprogesterone isprepared as follows:

In the manner described above, 16-methylene-17ot-hydroxy 4,9(11)pregnadiene-3,20-dione is reacted with chlorine in carbon tetrachloridein the presence of pyridine. The resultant product is isolated asdescribed and crystallized from acetone-hexane to give 9x,11,B-dichloro-16-methylene-l7a-hydroxyprogesterone, which, in turn, is reacted withacetic acid and trifluoracetic anhydride in the manner of Example 7 togive 9a,11fl-dichloro-16-methylene-l7a-hydroxyprogesterone l7-acetate.

(B) In a manner similar to that described in the first paragraph above,treat 6OL-Ch1OI'O-'16-II16tl'1yl6I16-17OL-acetoxy-9(ll)-dehydroprogesterone with chlorine in carbon tetrachloridein the presence of pyridine. Isolate and purify the resultant product ina manner similar to that described to give'6a,9a,1lfi-trichloro-l6-methylene- 17a-acetoxyprogesterone.

EXAMPLE 15 6ot-chloro-9u-bromo-11p,17u-dihydroxy-16-methyleneprogesterone 17-acetate To a mixture of 0.2g. of 6a-chloro-l6-methylene- 17a-hydroxy-4,9( 11)-pregnadiene-3,20-dione l7-acetate in ml. of dioxane (which has beenpurified by refiuxing over sodium followed by distillation) and 2 ml. ofwater is added 0.07 g. of N-bromoaectamide and 1 ml. of 1.5 N perchloricacid. The mixture is allowed to stand for 2 hours, then a solution of0.2 g. of sodium sulfite in 2 ml. of water is added and the mixture isextracted with methylene chloride. The organic extracts are combined,washed with water, dried over magnesium sulfate and evaporated to aresidue which is crystallized from acetone to give6a-chloro-9a-bromo-1lfl,17adihydroxy-16-methyleneprogesterone17-acetate.

EXAMPLE l6 6-substituted-16-methylene-17a-acetoxy-6-dehydroprogesteroneTwo grams of 6a-methyl-16-methylene-17a-hydroxyprogesterone 17-acetateand 5 g. of chloranil in 60 m1. of ethyl acetate and 15 ml. of aceticacid are heated at reflux temperature for 13 hours under an atmosphereof nitrogen. The reaction mixture is evaporated to a residue andextracted with ethyl acetate. The organic extracts are combined withcold 7% aqueous sodium hydroxide, then with water, dried over magnesiumsulfate, filtered and evaporated to a residue which is crystallized fromacetone-hexane to give6-methyl-16-methylene-17ahydroxy-4,6-pregnadiene-3,ZO-dione 17-acetate.

In similar manner, 6u-chloro-16-methylene-17u-hydroxyprogesterone17-acetate is reacted with chloranil in ethyl acetate and acetic acid.The resultant product is isolated as described and crystallized fromethylene chloride to give 6-chloro-16-methylene-l7a-hydroxy-4,6-pregnadiene-3,20-dione 17-acetate.

24 EXAMPLE 17 16-butylidene- 17 a-hydroxypro gesterone 17-acetate and16-ethylidene-17a-hydroxy-4,9(11 pregnadiene-3 ,20- dione l7-acetate (A)16a-alkyl-5-pregnen-3 B-ol-20-one 3-acetate and the 9(11)-dehydroanalog.3.6 grams of 5,16-pregnadien-3fi-ol-20-one 3-acetate in 20 ml. ofdry toluene is added to a Grignard reagent prepared from 10.5 g. ofbutyl iodide and 1.8 g. of magnesium in 40 ml. of ether, and containing200 mg. of cupric chloride. The reaction mixture is distilled until avapor temperature of C. is reached. The distillation is then stopped,and the reaction temperature maintained at 100 C. for 5 hours. Themixture is cooled, poured into ice and an aqueous solution of ammoniumchloride, and the solvent layers separated. The organic layer isdistilled in vacuo to a residue which is chromatographed on Florisil.Eluates ranging from 15% ether-in-hexane to 35% etherin-hexane arecollected and evaporated. The resultant residue is dissolved in 20 ml.of dry pyridine and 3 ml. of acetic anhydride and allowed to stand atroom temperature for 5 hours. Water is added. A precipitate resultswhich is filtered and crystallized from acetonehexane to give16a-n-butyl-S-pregnen-3,8-ol-20-one 3- acetate.

In a similar manner, 5,9(11),l6-pregnatrien-3fi-ol-20- one 3-acetate isreacted with ethyl magnesium iodide and subsequently esterified to givet-fl1y1-5,9(11)- pregnadien-BB-ol-ZO-one 3-acetate.

(B) 16a-alkyl-17a-bromo-5-pregnen 3 8-ol-20-one 3- acetate and the9(11)-dehydro analog.One gram of the 16u-n-butyl-5-pregnen-35-ol-20-oneS-acetate is dissolved in 10 ml. of acetic acid and there is added 2.1equivalents of bromine in acetic acid. When the bromine color isdischarged, 0.5 g. of sodium iodide in 3 ml. water is added. Thesolution is warmed at 30 C. for 20 minutes, cooled and then diluted withwater. A precipitate results which is filtered, Washed with water, driedand crystallized from aqueous acetone to give 16a-n1'butyl-17a-bromo-5-pregnen-35-ol-20-one 3-acetate.

In a similar manner, 16a-ethyl-5,9(11)-pregnadien-3/3- 01-20-one3-acetate is reacted with 3:1 equivalents of bromine in acetic acid andthe resultant product treated with l g. of sodium iodide and purified togive 16aethyl-17a-'bromo-5,9(11) pregnadien 3fl-ol-20-one 3- acetate.

(C) 16-alkyl-5,16-pregnadien 3fi-ol-20-one 3-acetate and the9(11)-dehydro analog-One gram of the 16an-butyl-17a-bromo-5-pregnen3B-ol-20-one 3-acetate is refluxed in 20 ml. of dimethylformamide undera nitrogen atmosphere for 3 hours. The reaction mixture is cooled, thenpoured into ice-water containing excess hydrochloric acid, and extractedwith methylene chloride. The extracts are combined, washed with water,dried over magnesium sulfate and evaporated to a residue which ischromatographed over Florisil. Eluates ranging from 10% ether-in-hexaneto 30% ether-in-hexane are combined and evaporated to a residue which iscrystallized from methylene chloride-hexane to give l6-n-butyl-5,16-pregnadien-3fl-ol-ZO-one 3-acetate.

Similarly, 160t-6thyl-1706 bromo-5,9(11)-pregnadien- 3/8-ol-20-one3-acetate is reacted with dimethylformamide to give16-ethyl-5,9(11),16-pregnatrien-3fi-ol-20-one 3- acetate.

(D) 16/i-n-butyl-16u,l7a-oxido 5 pregnen-Bfi-ol- 20-one and16,8-ethyl-16a,17u-oxido-5,9(11)-pregnadien- 3fl-ol-20-one.-In a mannersimilar to that described in Example 9C,16-n-butyl-5,16-pregnadien3/3-ol-20-one 3- acetate is reacted withhydrogen peroxide in an alkaline solution. The resultant product isisolated and purified as described to give16/3-n-butyl-16a,17a-oxido-5-pregnen- 318-01-20-0ne.

Similarly, 16-ethyl-5,9(11),16 pregnatrien-3fi-ol-20- one 3-acetate isreacted with alkaline hydrogen peroxide in the manner of Example 9C togive 16/3-ethyl-16a, 17a-0XidO-5,9( 11 )-pregnadien-3fl-ol-20-one.

(E) 16/8-n-butyl-16a,17a-oxidoprogesterone and 165-ethyl-16a,17a-oxido-9(11) dehydroprogesterone.ln a manner similar tothat described in Example 5B, 16 3-nbutyl-l6a,17a-oxido 5pregnen-3/3-ol-20-one is reacted with aluminum isopropoxide in thepresence of cyclohexanone to give16fi-n-butyl-16a,17a-oxidoprogesterone.

Similarly, 16 3-ethyl-16a-17a-oxido-5,9(11)-pregnadien- 3fl-ol-20-one isreacted with aluminum isopropoxide in the presence of cyclohexanone togive 16fi-ethyl-16a,17aoxido-4,9(11)-pregnadiene-3,20-dione.

(F) l6-butylidene 17a hydroxyprogesterone and 16- ethylidene-17a-hydroxy9(11) dehydroprogesterone. In a manner similar to that described inExample 6B, each of 16B-n-butyl-16a,17u-oxidoprogesterone and 163-ethyl-16u,17a-oxido-4,9( 11)-pregnadiene-3,20-dione is reacted withhydrobromic acid in acetic acid to give 16-butylidene-17u-hydroxyprogesterone and 16-ethylidene- 17a-hydroxy-9( 1 1-dehydroprogesterone, respectively.

(G) 16-butylidene-17a hydroxyprogesterone 17-acetate and 16 ethylidene170a hydroxy-9(11)-dehydroprogesterone 17-acetate.In the manner ofExample 7, each of 16 -butylidene-17a-hydroxyprogesterone and 16-ethylidene-17u-hydroxy-9 (l 1)-dehydroprogesterone is reacted Withacetic acid and trifluoroacetic anhydride to give16-butylidene-17a-hydroxyprogesterone 17-acetate and16-ethylidene-17a-hydroxy-9( 1 1)-dehydroprogesterone l7-acetate,respectively.

EXAMPLE 18 16-methylene-17a-hydroxy-2l-fluoroprogesterone and the17-acetate ester thereof (A) 16-methylene 17a hydroxy 21iodoprogesterone.To a solution of 0.5 g. of16-methylene-17a-hydroxyprogesterone in 5.6 ml. of tetrahydrofurane and3.4 ml. of methanol add 0.75 g. of calcium oxide (finely ground) and0.75 g. of iodine. The initial dark brown color slowly changes to a paleyellow over a minute period. Allow the reaction solution to stand anadditional hour then dilute with methylene chloride. Filter and thenwash the filtrate successively with a solution of 3% sodium iodide then4% sodium thiosulfate and with water. Evaporate the organic solution toa residue comprising 16-methylene 17a hydroxy-2l-iodoprogesterone.Purify by crystallization from acetone-ether.

In a similar manner, treat each of the following with iodine and calciumoxide:

6a-methyl-16-methylene-17a-hydroxyprogesterone,

16B-methyl-16a,17a-oxidoprogesterone,

9a,1IB-dichloro-l6-methylene-17u-hydroxyprogesterone,

6a,9a, l lfl-trichloro-16-methylene-17a-hydroxyprogesterone, and

6a,methyl-9a-fluoro-1 Iii-hydroxy-16-methylene-17aacetoxyprogesterone.

Isolate and purify the respective resultant products in a manner similarto that described above to obtain, respectively,

6a-methyl-16-methylene-17a-hydroxy-2l-iodoprogesterone,

16fl-methyl-16a,17u-oxido-2l-iodoprogesterone,

9a,1lB-dichloro-Z1-iodo-16-methylene-17a-hydroxyprogesterone,

6a,9oc,1 1 3-trichloro-21-iodo-16-methylene-17ahydroxyprogesterone, and

6a-methyl-9a-fluoro-2l-iodo-l1 3-hydroxy-16-methylene-17a-acetoxyprogesterone.

(B) 16 methylene 17a hydroxy-2l-fluoroprogesterone.To a solution of 0.5g. of 16-methylene-17whydroxy-Zl-iodoprogesterone in 100 ml. ofacetonitrile containing 1 ml. of water add a 50% aqueous solution of 1.5g. of silver fluoride. Warm the mixture at 3040 C. for 4 hours thenfilter and pour the filtrate into water. Filter the resultantprecipitate and crystallize from acetone-hexane to obtain16-methylene-l7a-hydroxy-2l-fluoroprogesterone.

In a manner similar to that described above, treat with an aqueoussilver fluoride solution each of the 21-iodol6-methyleneprogesteronederivatives prepared in the second paragraph of Example 18A. Isolate andpurify the resultant products in a manner similar to that describedabove to obtain respectively,

6a-methyl-l6-methylene-17a-hydroxy-2l-fluoroprogesterone,

16/3-methyl-16a,17a-oxido-2l-fiuoroprogesterone,

9a,1 lfi-dichloro-Zl-fluoro-l 6-methylene-17a-hydroxyprogesterone,

6a,9ot,1 lfi-trichloro-Z 1-fluoro-l6-methylene-17ahydroxyprogesterone,and

6a-methyl-9u,2 l-difluoro-l1,8-hydroxy-16-methylene-17aacetoxyprogesterone.

(C) 16 methylene 17m acetoxy-2l-fluoroprogesterone.In a manner similarto that described in Example 7 treat 16methylene-17ot-hydroxy-2l-fluoroprogesterone with acetic acid andtrifluoroacetic anhydride to yield 16-methylenel7a-acetoxy-21-fluoroprogesterone.

In a similar manner treat each of the Not-hydroxy compounds prepared inExample 18A and in the second paragraph of 18B above with acetic acidand trifluoro acetic anhydride to obtain, respectively,

6u-methyl-16-methylene-l7a-acetoxyprogesterone, 9a, 1IB-dichloro-16-methylenel7a-acetoxyprogesterone,

and 6a,9oc,1 1 fi-trichloro-l6-methylene-17a-acetoxyprogesterone.

EXAMPLE 19 6a-methyl-16-methylene-17u-hydroxy-4,9- 1 l)-pregnadiene-3,20-dione and the 17a-acetate ester thereof (A) 6a-methyl11a,17a dihydroxy 16 methyleneprogesterone.6a-methyl-16 methylene 17ahydroxyprogesterone is microbiologically hydroxylated as follows. Aculture of Rhizopus nigicans (A.T.C.C. 6227b) is maintained on 1% yeastextract, 1% cerelose agar at 28 C. Ten 300 ml. Erlenmeyer flasks eachcontaining ml. aliquots of the following sterile medium: 20 g. cerelose,5 g. protease peptone No. 3, 5 g. soybean meal, 5 g. sodium chloride, 5g. mono-potassium diacid phosphate and 3 g. yeast extract in suflicientwater to provide a liter of solution and adjusted to pH 6.8 areinoculated with a spore suspension of Rhizopus nigricans from the agarslants and incubated on a shaker at 280 r.p.m. at 28 C. From 24-48 hoursafter inoculation, 25 mg. of 6ot-methyl- 17a hydroxy-16methyleneprogesterone in 100 ml. of methanol are added to each flask,and shaken at about 28 C. for a period of one to two days. The flasksare vremoved from the shaker when the conversion to the Ila-hydroxysteroid is completed, as indicated by a paper chromatography techniquewhich is outlined by Bush, Journal of Biochemistry, 50, 370 (1952) andmodified by Shull, Paper Chromatograph of Steroid Fermentation Products,126th Meeting of the American Chemical Society, Sept. 12-17, 1954, NewYork, N.Y., section 9A, paper No. 24. The contents of the flasks arecombined and extracted with methylene chloride. The extracts are driedover sodium sulfate, filtered, and evaporated to a residue which iscrystallized from acetone-hexane to give 601- methyl-lla,Not-dihydroxy-16-methyleneprogesterone.

(B) 6a-methyl-1la, l7a-dihydroxy-16-methylene progesterone 11-p-toulenesulfonate.-In the manner described in Example 108,6a-methyl-11a,17a-dihydroxy-16- methyleneprogesterone is reacted withp-toluenesulfonyl chloride and pyridine in chloroform. The resultantproduct is isolated as described and crystallized from ethanol to give6a-methyl-11a,17a-dihydroxy-16 methylene-progesteronell-p-toluenesulfonate.

(C) 6a-methyl-16-methylene-17a-hydroxy 4,9 (ll)- 27pregnadiene-3,20-dione.-In the manner of Example C6a-methyl-11a,17o-dihydroxy-16 methyleneprogesteronell-p-toluenesulfonate is reacted with sodium acetate in acetic acid. Theresultant product is isolated as described and crystallized fromacetone-hexane to give 6a-methyl- 16-methylene-17a-hydr0xy4,9(11)-pregnadiene 3,20 dione.

(D) 6a-methyl-16-methy1ene 17cc acetoxy 4,9(11)-pregnadiene-3,20-dione.-In a manner similar to that described in Example7, the l7a-hydroxy-4,9(11)-pregnadiene of Example 19C is reacted withacetic acid and trifluoroacetic anhydride to give6a-methyl-16-methylene- 17a-hydroxy-4,9(11)-pregnadiene-3,20-dione17-acetate.

By substituting other lower alkanoic acids such as caproic and valericfor acetic acid in the above procedure, the corresponding 17-loweralkanoates are obtained, i.e. 6a-methyl16-methylene-17u-hydroxy 4,9(11)pregnadiene-3,20-dione caproate and 6a-methyl-16-methylene-17a-hydroxy-4,9(11)-pregnadiene-3,20-dione-17valerate.

EXAMPLE 9a,1lfi-dichloro-16-ethylidene-17a-acetoxyprogesterone To asolution of 1.0 g. of 17a-hydroxy-16-ethylidene-4,9(11)-pregnadiene-3,20-dione 17-acetate and 4.0 g. of lithium chloridein 50 ml. of glacial acetic acid cooled to 10 C. is added 250 mg. ofhydrogen chloride in 10 ml. of tetrahydrofuran followed by 0.5 g. of 93%N-chlorosuccinimide. The solution is stirred in the dark at roomtemperature for 20 minutes and then is poured into icewater withstirring. A yellow precipitate separates, which is filtered, washed withwater, triturated with ether and crystallized from acetone-hexane togive 9a,11fi-dichloro- 16-methylene-l7ot-hydroxyprogesterone 17-acetate.

In a similar manner, 6a-methyl 16 methylene 170:acetoxy-4,9(11)-pregnadiene-3,20-dione is reacted with N-chlorosuccinimide, hydrogen chloride and lithium chloride and theresultant product isolated and purified in a manner similar to thatdescribed above to give 6a-methyl-9a-l1fidichloro-l6-methylene-17a-acetoxyprogesterone.

EXAMPLE 21 9a-halogeno-1 l-hydroxyl6-methylene-17a-acetoxyprogesteroneand the 6ct-methyl analog thereof (A)9a-bromo-1p-hydroxy-16-methylene-17u acetoxyprogesterone and the6a-methyl analog thereof.In a manner similar to that described inExample 15, treat each of the following with N-bromoacetamide andperchloric acid in aqueous dioxane:

6a-methyl-16-methylene-17a-hydroxy-4,9( 11 pregnadiene-3,20-dione16-methylene-17a-hydroxy-4,9 1 l-pregnadiene- 3,20-dione 17-acetate, and

16-methylene-l7a-hydroxy-4,9 1 1 -pregnadiene- 3 ,20-dione.

Isolate and purify the respective resultant products in a manner similarto that described to obtain, respectively:

Gar-methyl-9a-bromo-1 1/3-17a-dihydroxy-16-methyleneprogesterone,

9a-bromo-18 8,Not-dihydroxy-16-methyleneprogesterone 17-acetate, and

9a-brom0-11fi-17ot-dihydroxy-16-methyleneprogesterone.

(B) 6oz methyl 95,115 oxido-16-methylene-17a-hydroxyprogesterone17-acetate.-To 0.3 g. 6a-methyl-9abromo 115,170 dihydroxy 16methyleneprogesterone 17-acetate in 30 m1. of acetone is added 0.3 g. ofpotassium acetate. The reaction mixture is refluxed for 6 hours, thenthe acetone is distilled. Water is added to the resultant residue. Asolid separates which is filtered and crystallized from methauol-waterto give 6a-methyl-9fl,llfioxido-16-methylene-17a-hydroxyprogesterone17-acetate.

23 In a similar manner, treat each of the following with potassiumacetate in acetone:

9a-bromo-1 lfi-hydroxy-16-methylene-17aacetoxyprogesterone,

9a-bromo-1 lfi,17a-dihydroxy-16-methylene progesterone, and

6a-chloro-9a-bromo-1 1,8-hydroxy-16-methylene-17aacetoxyprogesterone.

Isolate and purify the resultant products in the manner described toobtain, respectively:

96,1 lfi-oxido-16-methy1ene-l7a-acetoxyprogesterone,

9,8,1 lfl-oxido-16-methylene-17a-hydroxyprogesterone, and

6a-chloro-9B,11/3-oxid0-16-methylene-17a-acetoxyprogesterone.

(C) 6a methyl 9a fiuoro 115,170: dihydroxy-16- methyleneprogesteronel7-acetate.To 3.5 g. hydrogen fluoride in 20 ml. of chloroform and 0.6ml. of tetrahydrofuran at 10 C. is added 2 g. of 6u-methyl-9B,11/3-oxido-17a-hydroxy-16-methyleneprogesterone 17 acetate. The reactionmixture is kept at -10 C. for 3 hours, then poured into aqueous sodiumcarbonate solution. The organic solvent layer is separated from thewater and evaporated to a residue which is crystallized from methanol togive 6a-methyl-9a-fluoro-115,17a-dihydroxy-16-methyleneprogesterone17-acetate.

In similar manner, treat each of the 95,11,8-oxido-16-methyleneprogesterones prepared as described in the second paragraph ofExample 21B with aqueous sodium carbonate solution. Isolate theresultant respective products in a manner similar to that describedabove to obtain,

respectively:

9oc-fillOIO-1 1 3-hydroxy-16-methylene-17aacetoxyprogesterone,

9a-fil10IO-1 1,3,17a-dihydroxy-1fi-methyleneprogesterone,

and

6a-chloro-9a-fiuoro-1IB-hydroxy-16-methylene-17a.-

acetoxyprogesterone.

(D) 6a methyl 9oz chloro 1113,1704 dihydroxy-16- methyleneprogesterone17-acetate.-A solution of 0.2 g. of 6u-methyl9;8,11;8-0xido 16-methylene17a hydroxyprogesterone 17-acetate in 30 ml. of alcohol-free chloroformis saturated at 0 C. with anhydrous hydrogen chloride and the mixtureallowed to stand at 0 C. for 6 hours. The solvent is distilled in vacuofrom the reaction mixture leaving a residue which is crystallized fromacetone to give 6a-methyl-9wchloro-11/3,17a-dihydroxy-16-methyleneprogesterone 17-acetate.

In a similar manner, treat each of the 96,11,8-oxido-16-methyleneprogesterones as described in the second paragraph of Example21B with anhydrous hydrogen chloride in chloroform. Isolate and purifythe resultant respective products in a manner described in above Example21D to obtain, respectively:

9a-chloro-1 1 8-hydroxy-16-methylene-17a-acetoxyprogesterone,

9a-chl0ro-1 118,17a-dihydroxy-16-methyleneprogesterone,

and

6a,9oa-diChlOrO-1 lfl-hydroxy- 1 G-methylene- 17a-acetoxyprogesterone.

We claim:

1. In a process for the preparation of 16-1ower alkylidene-17a-hydroxycompounds of the pregnane series, the step which comprises reacting a16B-lower alkyl-16a,17aoxido compound of the pregnane series having anoxygenated function of 03 selected from the group consisting of3fl-hydroxy, 3/3-hydrocarboncarboxy and 3,8-hydrocarbonsulfonyloxy witha non-oxidizing strong acid in a non-aqueous solvent.

2. The process according to claim 1, wherein the lower alkyl group ismethyl.

3. The process according to claim 1 wherein the 165- loweralkyl-16a,l7a-compound of the pregnane series is a member selected fromthe group consisting of 16oL,l7uoxido-16/9-methylpregnane-3[3-ol-20-oneand the 3-acetate ester thereof.

4. The process according to claim 1 wherein the 16;?- loweralky1-16oz,l7a-OXiCl0 compound of the pregnane series is a memberselected from the group consisting of16a,17a-oxido-16fl-methyl-allopregnane 35 ol 20 one and the 3-acetateester thereof.

5. The process according to claim 1, wherein the strong acid is hydrogenbromide.

6. In a process for the manufacture of 16-methylene steroids, the stepwhich comprises reacting a member of the group consisting of 16 8 methyll60z,l7ot oxido-S- pregnen-3-ol-20-one and its 3-acetate with an acidselected from the group consisting of hydrogen chloride, hydrogenbromide, and para-toluenesulfonic acid; to effect opening up of theoxido ring with a formation of 17a-hydroxyl and a 16-methy1ene group.

7. In a process for the preparation of a 17a-hydroxy-16-methylene-pregn-4-ene-3,20-dione from a 16 methyl pregnadiene havinga A -double bond, the steps comprising selectively epoxidizing the A-double bond with alkaline hydrogen peroxide to give a1606,1706'fiPOXld6, and cleaving the l6a,l7a-epoxide with hydrogenbromide.

8. In a process for the preparation of 16,6-methy1-17ahydroxy compoundsof the pregnane series, the step which comprises reacting a memberselected from the group consisting of 16a,17a-oXido-16,Bmethyl--pregnen-304-01-20- one and the 3-acetate ester thereof with anon-oxidizing strong acid in a non-aqueous solvent.

9. A compound of the group consisting of 35,17a-dihydroxy-l-loweralkylidene-20-keto-pregnanes and pregnenes and the 3-lower alkanoatesthereof.

10. A Sfl-hydroxy-S-pregnene compound according to claim 9, wherein said16-lower alkylidene is 16-methylene, said compound being 16methylene-S-pregnene-Iifi,17adiol-ZO-one.

11. A S S-lower alkanoyloxy-S-pregnene compound according to claim 9,wherein said 16-lower alkylidene is 16- -methylene, said compound being16 methylene-S-pregnene-3fl,17u-diol-20-one 3-lower alkanoate.

12. A 3fi-lower alkanoyloxy-S-pregnene compound according to claim 9,wherein said 16-lower alkylidene is 16-methylene and said 3-loweralkanoate is 3-acetate, said compound being16-methylene-5-pregnene-3,8,17a-di01-20- one 3-acetate.

13. A 313 hydroxy pregnane compound according to claim 9, wherein said16-lower alkylidene is 16-methylene, said compound being16-methylenepregnane-3fl,l7a-diol- 20-one.

14. A 35 lower alkanoyloXy-pregnane compound according to claim 9,wherein said 16-lower alkylidene is 16- methylene, said compound being16-methylenepregnane- 3fl,l7a-diol-20-one 3-lower alkanoate.

15. A 35 hydroxy allopregnane compound according to claim 9 wherein said16-1ower alkylidene is 16-methylene, said compound being16-methyleneallopregnane-3p, 17a-diol-20-one.

16. A 3fl-lower alkanoyloxy allopregnane compound according to claim 9wherein said 16-10wer alkylidene is 16 methylene, said compound being 16methyleneallopregnane-35,17a-diol-20-one 3-lower alkanoate.

17. The process according to claim 1 wherein the 1618- UNITED STATESPATENTS 3,379,745 4/1968 Oliveto et al 260397.47 3,345,387 10/1967 Taubet al. 260397.45 3,296,075 1/ 1967 Kirk et al. 16774 ELBERT L. ROBERTS,Primary Examiner US. Cl. X.R.

22 33 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.5,519,619 D t d July 7, 97

Inventor-(s) E. B. Hershberg, E. P. Oliveto and R. C. Rausser It iscertified that error appears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

Column 1, line 19, "having a. valuable" should read having valuableColumn 2, line 72, "bromide" should read bromine Column 5, line 10, "anddesired" should read any desired Column 3, line 27, "-l6-pregnanes"should read -l6-pregnenes Column 9, line 27, "-Ct.6a-" should read -l,t- Column 10, line 26, "5-keo-" should read j-keto- Column 10, line +8,"-lY-acyloxprogesterone, should read -l7-acyloxyprogesterone, Column 11,line 21, "-lTG-flcyloxprogesterone" should read -l7CtecyloxyprogesteroneColumn ll, line 55, "The 6fi-chloro and 6B-fluoro-l6-lower alkylidene-"should read The novel 9oz,llB-dihalogeno-l6-lower alkylidene- Column ll,line 1&5, "methyl; and at the 2-car'bon being fluorine or iodine. shouldread methyl; at the l'I-car'bon being hydroxy or acyloxy; and at the2l-carbon being fluorine or iodine. Column 15, lines l-j- -l l,"60!,9(1-difluoro-l6-fluoro-llfi,lTOt-diecetoxyl6-methyleneprogesterone5should read 6a,9a-d1f1uoro-l6- methylene-11B,l'm-diacetoxy-progesterone; 6(1-chloro-90t-fluoro-11B,l70t-diecetoxy-lS-methyleneprogesterone; Column 15, line 65,"-l'TCl-hydroxy-" should. read -l-acetoxy- Column 15, line 70,"-16-methylene-l7-" should read -l6- methylene-lTOt- Column 1 line 19,"The l'YOt-hydropregnadiene" should read The lYOK-hydroxypregnadieneColumn 1 line 32, "-l7-hydroxy-" should read -l70-hydroxy- Column 1 line36, "-6a-fluoro-" should read -60t-chloro- Column 1 line 57,"-lT-acetoxyprogesterone, should read -1"(a-acetoxyprogesterone, Column1 1-, lines +5, M, and +5, "-6-dehydroprogesterone, end 6-chloro-"should read 6-dehydroprogesterone, 6-chloro- Column 16, lines 5 and 6,"followed by dihydrobromination" should read followed bydidehydrohromination Column 16, line 11, "and 9,l1-oxide," should readand 9,ll-oxido, Column 20, line 60, "poured ice-water, should readpoured into ice water, Column 21, Example 12, line 50,

Lhydroxyl-" should read -l'('0b-hydroxy- Page 2 *zg gg UNITED STATESPATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 5,519,619 Dated July7: 97

Invent0r(s) E. B. Hershberg, E. P. Oliveto and R. C. Rausser It iscertified that error appears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

Column 22, Example 15, line 1 "-5,6-hichloro-" should read-5,6-d1chloro- Column 25, Example 15, line +5, "N-bromoaectamide" shouldread ---N-'bromoacetamide Column 23, Example 16, line 75, "ethylene"should read methylene Column 26, Example 19, line 68,"-p-toulenesulfonate" should read p-toluenesulfonate Column 27, Example21, line +5, "-ll-hydroxy-" should read -1lB-hydroxy Column 27, Example21, line +6, "-lB-hydroxy-" should read -llB-hydroxyall WLE} Add 5 5;.LB

OST 2 )1970 (SEAL) Atteat:

mmummhmn; mm]: swam m Officur Commissioner of Patants

